6-(hydronaphtyl-1-ethyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones and the corresponding hydroxy acids

ABSTRACT

Compounds of either of general formulae (I) and (II), wherein: R 1  represents a C 1-8  alkyl, C 3-8  cycloalkyl, C 3-8  cycloalkyl(C 1-8 )alkyl, C 2-8  alkenyl, or C 1-6  alkyl substituted phenyl group; R 2  represents a C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl group or a C 1-5  alkyl, C 2-5  alkenyl or C 2-5  alkynyl group substituted with a substituted phenyl group; R 3  represents a hydrogen atom or a substituent R 4  or M; R 4  represents a C 1-5  alkyl group, or C 1-5  alkyl group substituted with a group chosen from substituted phenyl, dimethylamino and acetylamino; R 5  represents a hydrogen atom or a methyl or ethyl group except that when R 2  is methyl then R 5  is not methyl; M represents a cation capable of forming a pharmaceutically acceptable salt; Q represents C═O or CHOH; and each of a, b, c, and d, is independently a single or double bond except that when a and c are double bonds then b is a single bond; are inhibitors of the enzyme 24 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the rate limiting enzyme in the biosynthesis of cholesterol in mammals including man, and as such are useful in the treatment of hypercholesterolemia in general and arteriosclerosis, familiar hypercholesterolemia or hyperlipidemia in particular.

This invention relates to pharmaceutically active compounds, which aresubstituted decalins. The compounds of the present invention areinhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase(HMG-CoA reductase), the rate limiting enzyme in the biosynthesis ofcholesterol in mammals including man, and as such are useful in thetreatment of hypercholesterolaemia and hyperlipidaemia. Clinicalevidence shows that reduction of serum cholesterol levels lead to adecreased risk of heat disease.

The natural fermentation products compactin (disclosed by A. Endo, etal. in Journal of Antibiotics, 29, 1346-1348 (1976) and mevinolin(disclosed by A. W. Alberts, et al. in J. Proc. Natl. Acad. Sci. U.S.A.,77, 3957 (1980)) are very active antihypercholesterolaemic agents whichlimit cholesterol biosynthesis by inhibiting the enzyme3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, therate-limiting enzyme and natural point of cholesterolgenesis regulationin mammals, including man. Compactin (R=H, a=double bond) and mevinolin(R=α-CH₃, a=double bond; also known as lovastatin) have the structuresshown below: ##STR1##

Also known in the art are the natural products dihydrocompactin (R=H,a=single bond) disclosed by Y. K. T. Lam et al., Journal of Antibiotics,34, 614-616 (1981), dihydromevinolin (R=α-CH₃, a=single bond) disclosedby G. Albers-Schonberg et al., Journal of Antibiotics, 34, 507-512(1981), and eptastatin (R=β-OH, a=double bond) disclosed by N. Serizawaet al., in Journal of Antibiotics, 36, 604-607 (1983).

U.S. Pat. No. 4,293,496 (Willard) disclosed a number of semisyntheticanalogues of mevinolin having the structure ##STR2## where the dottedlines represent single or double bonds and R is C₁₋₈ straight chainalkyl, C₃₋₁₀ branched chain alkyl except (S)-2-butyl, C₃₋₁₀ cycloalkyl,C₂₋₁₀ alkenyl, C₁₋₁₀ CF₃ substituted alkyl, halophenyl, phenyl C₁₋₃alkyl and substituted phenyl C₁₋₃ alkyl.

U.S. Pat Nos. 4,444,784, 4,661,483, 4,668,699 and 4,771,071 (Hoffman)disclose compounds of similar structure where the R group contains extrafunctional groups, for example ether, amide and ester groups. In J. Med.Chem., 29, 849-852 (1986), W. F. Hoffman et al. report the synthesis andtesting of a number of the analogues referred to above, the preferredcompound (now known as simvastatin) have the structure ##STR3##EP-A-0251625 (Inamine) discloses compounds of structure ##STR4## where Ris similar to the corresponding group in the compounds described above,R¹ is a group of formula CH₂ OH, CH₂ OCO.R³, CO₂ R⁴ or CO.NR⁶ R⁷ whereinR³, R⁴, R⁶, and R⁷ can cover a range of alkyl, alkoxy, or aryl groups,and the dotted lines represent single or double bonds. Only one of thesecompounds, in which R¹ is CH₂ OCO.NHPh, R is 1,1-dimethylpropyl and aand c are double bonds has a disclosed activity better than that ofmevinolin. In general, the above patent publications also covercompounds in which the delta lactone has been hydrolysed to a deltahydroxy acid or a salt of that acid.

EP-A-0142146 disclosed compounds of structure ##STR5## where E is --CH₂--CH₂ --, --CH═CH-- or --(CH₂)₃ -- and Z is (amongst others) asubstituted decalin system of the same form as in those compoundsreferred to above.

None of the cited patents and articles disclose or suggest thepossibility of preparing the compounds of the present invention. Theunique pattern of substituents on the decalin ring system differs fromthe cited art, whilst the compounds exhibit potent HMG-CoA activity.

The present invention provides novel decalin based compounds which arepotent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase and, therefore, are useful in the treatment orprevention of hypercholesterolaemia, hyperlipoproteinaemia andatherosclerosis.

According to a first aspect of the invention, there is provided acompound of either of general formula I and II: ##STR6## wherein: R¹represents a C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl(C₁₋₈)alkyl,C₂₋₈ alkenyl, or C₁₋₆ alkyl substituted phenyl group;

R² represents a C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, group or a C₁₋₅alkyl, C₂₀₅ alkenyl, or C₂₋₅ alkynyl group substituted with asubstituted phenyl grip;

R³ represents a hydrogen atom or a substituent R⁴ or M;

R⁴ represents a C₁₋₅ alkyl group, or a C₁₋₅ alkyl group substituted witha group chosen from substituted phenyl, dimethylamino and acetylamino;

R⁵ represents a hydrogen atom or a methyl or ethyl group, except thatwhen R² is methyl then R⁵ is not methyl;

M represents a cation capable of forming a pharmaceutically acceptablesalt;

Q represents C═O or CHOH; and

each of a, b, c, and d is independently a single or double bond exceptthat when a and c are double bonds then b is a single bond.

The term "C₁₋₈ alkyl" refers to a straight or branched chain alkylmoiety having one to eight carbon atoms, including for example, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl, dimethyl-propyl,hexyl, and octyl, and cognate terms (such as "C₁₋₈ alkoxy") are to beconstrued accordingly.

The term "C₃₋₈ cycloalkyl" refers to a saturated alicyclic moiety havingfrom 3 to 8 carbon atoms arranged in a ring and includes, for example,cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

The term "C₂₋₈ alkenyl" refers to a straight or branched chain alkylmoiety having one to eight carbon atoms and having in addition at leastone double bond, of either E or Z stereochemistry where applicable. Thisterm would include, for example, vinyl, 1-propenyl, 1- and 2-butenyl and2-methyl-2-propenyl.

The term "C₂₋₈ alkynyl" refers to a straight or branched chain alkylmoiety having one to eight carbon atoms and having in addition at leastone triple bond. This term would include, for example, propargyl, and 1-and 2-butynyl.

The term ¢substituted", as applied to a phenyl or other aromatic ring,means substituted with up to four substituents each of whichindependently may be C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, thiol, amino,halo (including fluoro, chloro, bromo, and iodo), trifluoromethyl ornitro.

The phrase "a pharmaceutically acceptable salt" as used herein and inthe claims is intended to include non-toxic alkali metal salts such assodium, potassium, calcium and magnesium, the ammonium salt and saltswith non-toxic amines such as trialkylamines, dibenzylamine, pyridine,N-methylmorpholine, N-methylpiperidine and other amines which have beenor can be used to form salts of carboxylic acids.

There are several chiral centres in the compounds according to theinvention because of the presence of asymmetric carbon atoms. Thepresence of several asymmetric carbon atoms gives rise to a number ofdiastereoisomers with the appropriate R or S designated stereochemistryat each asymmetric centre. General Formulae I and II and, whereappropriate, all other formulae in this specification are to beunderstood to include all such stereoisomers and mixtures (for exampleracemic mixtures) thereof.

Disregarding any asymmetric centres that may be present in the groupsR¹, R², R³ and R⁴, the preferred relative and absolute stereochemistryis as shown in formula III, mutatis mutandis. More specifically for thecompound III the Cahn, Ingold, Prelog designations for the absoluteconfigurations are 4'(R), 6'(R), 1(S), 2(S), 4a(R), 6(S), 8(S), 8a(S).##STR7## It is preferred that all of the compounds of general formulae Iand II should have (wherever possible) the same spacial orientation ofgroups at each chiral carbon atoms and therefore belong to the samestereochemical series. The R-S designation for each center may not beidentical to that found for compound III because of the details of thesequence rules for determining that designation. Clearly in compounds inwhich a or b are double bonds then the carbon atom labelled C-4a willnot be an asymmetric centre, and in compounds of Formula II in which Qin the group C═O then the carbon atom labelled C-6' is not an asymmetriccentre.

In compounds of Formula II in which Q is the group CHOH, the preferredstereochemistry is that in which the two carbon atoms bearing thehydroxy groups have the same spacial arrangement as the correspondingcarbon atoms in the lactone in compound III. The preferred isomer isreferred to as the syn diol.

Each M is preferably free from centres of asymmetry and is morepreferably sodium, potassium or ammonium, and most preferably sodium.For simplicity, each formula in which an M appears has been written asif M were monovalent and, preferably, it is. However, M may also bedivalent or trivalent and, when it is, it balances the charge of two orthree carboxylic acid groups, respectively. Thus Formula II and everyother formula containing an M embraces compounds wherein M is divalentor trivalent, e.g. compounds containing two or three monocarboxylate-containing anions per cation M.

Preferred compounds include those in which independently or in anycombination:

R¹ represents C₄₋₆ branched alkyl;

R² represents C₂₋₆ alkenyl or C₂₋₅ alkenyl substituted with substitutedphenyl;

R³ is R⁴

R⁴ represents C₁₋₅ alkyl and more preferably methyl or ethyl;

Q represents CHOH; and/or

b and d are both single bonds, and one or both of a and c are doublebonds.

A preferred subgroup or compounds of either general formula I or ofgeneral formula II are those wherein R¹ represents a C₄₋₆ branched alkylgroup; R² represents a C₂₋₆ alkenyl group; each of a and c independentlyrepresents a single or double bond; and each of b and d represents asingle bond. Illustrative compounds of this subgroup are:

(A) (1S,2S,4aR,6S,8S,8aS,4'R,6'R,2"S)-6'-{1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)oxy]-6-[(Z)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one

(B) Sodium (1S,2S,4aR,6S,8S,8aS,3'R,5'R,2"S)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)oxy]-6-[(Z)-prop-1-enyl]-1-naphthalenyl)-3',5'-dihydroxyheptanoate

(C) (1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(Z)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one

(D) (1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-but-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one

(E) (1S,2S,4aR,6S,8S,8aS,4'R,6'R,2"S)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)oxy]-6-[(E)-hex-1-enyl]-1-naphthalenyl)ethyl)-tetrahydro-4'-hydroxy-2H-pyran-2'-one

(F) (1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-hex-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one

Particularly preferred compounds of this subgroup are those wherein R¹represents a C₄₋₅ branched alkyl group; R² represents (E)-prop-1-enyl;and R⁵ represents methyl. Illustrative of this particularly preferredsubclass are:

(G) (1S,2S,4aR,6S,8S,8aS,4'R,6'R,2"S)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one

(H) Methyl (1S,2S,4aR,6S,8S,8aS,3'R,5'R,2"S)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3',5'-dihydroxyheptanoate

(J) Methyl (1S,2S,4aR,6S,8S,8aS,3'R,2"S)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1naphthalenyl)-3'-hydroxy-5'-oxoheptanoate

(K) (1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one

(L) Methyl (1S,2S,4aR,6S,8S,8aS,3'R,5'R)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3',5'-dihydroxyheptanoate

(M) Methyl (1S,2S,4aR,6S,8S,8aS,3'R)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3'-hydroxy-4'-oxoheptanoate

(N) Sodium (1S,2S,4aR,6S,8S,8aS,3'R,5'R)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3',5'-dihydroxyheptanoate

A second preferred subgroup of compounds are those wherein R¹ representsa C₄₋₆ branched alkyl group; R² represents a C₂₋₅ alkenyl substituted byan optionally substituted phenyl group, each of a and c independentlyrepresents a single or double bond; and each of b and d represents asingle bond. Illustrative compounds of this subgroup are:

(P) (1S,2S,4aR,6S,8S,8aS,4'R,6'R,2"S)-6'-{2-(1,1,4a,5,6,7,8,8a-octahydro-2-methyl-8[(2"-methyl-1"-oxobutyl)oxy]-6-[3-phenyl-(E)-prop-1-enyl]-1naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one

(Q) (1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[3-phenyl-(E)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one

For simplicity the compounds of Formula II may be subdivided accordingto the exact form of R³ and Q. Thus the compounds in which Q is thegroup C═O and R³ is M are considered to be compounds of the subgroupIIe, whereas if R³ is a group of formula R⁴ the ketones are in thesubgroup IIa. Compounds in which Q is the group CHOH and R³ is a groupof form R⁴ make up the subgroup IIb, when R³ is hydrogen the compoundsare of subgroup IIc, and when R³ is a group of formula M the compoundsare of the subgroup IId.

The present invention also provides novel processes for the preparationof compounds of general formulae I and II as well as certainintermediates in their preparation, as will now be described byreference to the drawings.

DESCRIPTION OF DRAWINGS

FIG. 1 shows reaction scheme I, which shows the interconversion ofcompounds of general formula I with subgroups IIa, IIb, IIc and IId andthe interconversion of compounds of general formula I with compounds ofgeneral formula IV;

FIG. 2 shows reaction scheme II, which shows a preparative route ofcompounds of subgroups IIa and IIe from compounds of general formulaXIV, which in turn are preparable form compounds of general formula VII;

FIG. 3 shows reaction scheme III, which shows a different preparativeroute of compounds of general formula XIV, this time from compounds ofgeneral formula XV;

FIG. 4 shows reaction scheme IV, which shows a preparative route ofcompounds of general formulae VII and XV from compounds of generalformulae XXI and/or XXII, which in turn may be prepared from compoundsof general formula XIX;

FIG. 5 shows reaction scheme V, which shows a further preparative routefor compounds of general formula XXII;

FIG. 6 shows reaction scheme VI, which shows a further preparative routefor compounds of general formula XXI; and

FIG. 7 shows reaction scheme VII, which shows a further route for thepreparation of compounds of general formula I.

The compounds of various subgroups IIa-IId of general formula II(hereafter referred to as general formula IIa to IId), and those ofgeneral formula I, may be prepared by the general reaction route shownin Scheme I in which R¹, R², R⁴, R⁵ and M are as previously defined.Unless the context otherwise requires, substituents in the generalformulae in Schemes I and II have the same values as the correspondingsubstituents in general formulae I and II.

According to a second aspect of the invention, there is provided aprocess for the preparation of a compound of either of general formulaeI and II, the process comprising:

(a) deprotecting and optionally reducing a compound of general formulaXIV as shown in Scheme II to form a compound of general formula IIa; or

(b) when R⁵ represents methyl, deprotecting a compound of generalformula LXXIII to form a compound of general formula I; and

(c) optionally after step (a) or (b) converting a compound of generalformula I or IIa directly or indirectly into another compound of generalformula I or II.

A ketone of general formula IIa may be reduced to a dihydroxy ester ofgeneral formula IIb by redaction of the ketone group with a reducingagent, such as those well known in the art, e.g. sodium borohydride,sodium cyanoborohydride, zinc borohydride, lithiumtri-s-butylborohydride or other similar reducing agents that will notreduce the ester functionality. Preferably, the reaction is carried outin such a manner as to maximize the production of the preferred synisomer of the compound of general formula IIb. The steroselectivereduction of compounds of general formula IIa is preferably carried outin two stages, in the first stage the ketone ester is reacted with atrialkylborane, preferably tri-n-butyl borane, or analkoxydialkylborane, preferably methoxydiethylborane orethoxydiethylborane (Chemistry Letters, 1987, 1923-1926) at ambienttemperature in an inert organic solvent such as tetrahydrofuran, diethylether, or 1,2-dimethoxyethane, and optionally in the presence of aprotic solvent such as methanol or ethanol, and preferably in a mixtureof tetrahydrofuran and methanol. The complex which is thus produced isthe reduced with sodium borohydride at a temperature between -78° C. and-20° C. The resulting compound of general formula IIb produced from thesteroselective reduction contains two asymmetric carbon atoms bearinghydroxyl groups in a syn configuration. Thus reduction of the ketoneradical under the conditions described herein produces mostly the synisomers of compounds of general formula IIb and only a small amount ofthe less preferred anti isomers.

The ratio of isomers produced will vary according to the specificcompound utilized and the reaction conditions employed. Normally, thisratio will be approximately 9:1 to 9.8:02. However, the use of anon-specific reduction method will normally produce a near 1:1 mixtureof diastereoisomers. Nevertheless, the mixture of isomers may beseparated and purified by conventional techniques and then converted tothe compounds of general formula I in a conventional manner well-knownto those skilled in the art.

Compounds of general formula IIb may be cyclised to the correspondinglactones of general formula I for example by heating in an inert organicsolvent such as benzene, toluene or xylene and azetropically removingthe alcohol which is produced. Preferably, the lactonisation is carriedout by heating the compound of general formula IIb with an acid,preferably p-toluenesulphonic acid, in benzene or toluene, evaporatingthe solvent and alcohol thus formed, and repeating the process until allof the compound of general formula IIb has been consumed. If therelative stereochemical configuration of the two carbon atoms bearingthe hydroxy groups are established as syn in general formula IIb, thenlactonisation will produce the preferred trans lactone of generalformula I, otherwise the lactonization will produce a mixture of transand cis lactones.

A compound of general formula IId may be prepared from a compound ofgeneral formula IIb or a compound of general formula I by hydrolysis,preferably hydrolysis with a base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide in a mixture of water and an organicsolvent such as methanol, ethanol or tetrahydrofuran at a temperaturebetween 0° C. and 50° C. inclusive, preferably at ambient temperature.The cation in compounds of general formula IId is usually determined bythe cation of the hydroxide employed; however, the cation may then beexchanged for another cation for example by treatment with ion-exchangeresin.

Compounds of general formula IIc may be obtained from compounds ofgeneral formula IId by neutralisation, for example carefulneutralisation with a mineral acid such as hydrochloric, sulphuric ornitric in aqueous solution, followed by extraction with an appropriateorganic solvent. Alternatively, the acids of general formula IIc may beobtained by treating compounds of general formula IId with an ionexchange resin. If the acids of general formula IIc are allowed to standin solution they slowly re-lactonise to the compounds of general formulaI. This process may be accelerated by heating a solution of the acidunder conditions that remove the water formed, such as in a Dean-Starkapparatus, or by stirring the solution with a drying agent such asanhydrous sodium sulphate, magnesium sulphate or molecular sieves.

Lactones of general formula I may, if desired, be hydrolysed in thepresence of an alcohol and a catalytic amount of acid, preferablyp-toluenesulphonic acid, to produce compounds of general formula IIb.

Compounds of general formulae I, IIb, IIc and IId may be converted tocompounds of general formula I in which the ester group containing R¹has been exchanged for another ester group, for example via ade-acylated intermediate using the methodology of U.S. Pat. No.4,444,784. Thus a compound of general formula I, IIb, IIc or IId may betreated for extended periods, for example 1-3 days, with an alkalinemetal hydroxide such as lithium hydroxide, sodium hydroxide or potassiumhydroxide in a solvent such as water or an alcohol, and preferably amixture of water and ethanol, until the ester group containing the groupR¹ is removed. Mild acid treatment then closes the lactone ring to givean alcohol of general formula IV. The secondary alcohol of generalformula IV is then selectively protected with a t-butyldimethylsilylgroup under standard conditions to give an intermediate alcohol ofgeneral formula V, as shown in Scheme I. Acylation, for example using anacid halide or anhydride in the presence of a mild base such astriethylamine or pyridine, or by using an acid and an activating agentsuch as carbodiimide and optionally using N,N-dimethylaminopyridine as acatalyst, in an inert solvent such as chloroform, followed bydeprotection of the secondary hydroxyl group using tetrabutylammoniumfluoride in tetrahydrofuran, buffered with acetic acid, gives a compoundof general formula I in which the original group R¹ has been exchangedfor a different group of formula R¹.

A ketone of general formula IIa may be prepared by the methods outlinedin Scheme II, in which R¹, R², R⁴, and R⁵ are as previously described,and p¹, p² and R¹¹ are defined below.

Compounds of Formula IIa wherein d is a double bond may be prepared byremoving the protecting group p² from compounds of formula XIV. This maybe achieved in the preferred cases in which p² is trialkylsilyl oralkyldiarylsilyl by the use of conditions that generate fluoride anions,and preferably by using tetrabutylammonium fluoride in tetrahydrofuranbuffered with acetic acid or hydrofluoric acid in aqueous acetonitrile.

Compounds of Formula IIa wherein d is a single bond may be obtained fromcompounds of Formula IIa wherein d is a double bond by reduction of thecarbon-carbon double bond of the enone system, using reagents andconditions that do not affect the other functional groups present.Examples of such reagents are sodium hydrogen telluride, triphenyltinhydride, or tri-n-butyltin hydride with a palladium or platinumcatalyst.

Compounds of Formula IIa wherein d is a single bond may also be preparedfrom enones of general formula XIV by reduction of the double bondfollowed by deprotection. For example it is possible to reduce thedouble bond in one reaction by treatment with such mixtures astri-n-butyltin hydride with a palladium or platinum catalyst, or with atrialkylsilane, preferably triethylsilane, and a catalyst such astris(triphenylphosphine)rhodium chloride [Wilkinson's catalyst] eitherneat, using an excess of the silane, or in an inert hydrocarbon solventsuch as benzene or toluene at a temperature between ambient and reflux,preferably 50°-70° C. The crude silyl enol ether thus produced istreated with hydrofluoric acid in aqueous acetonitrile to give thecompound general formula IIa in which d is a single bond.

However, the preferred method of transformation of compounds of generalformula XIV is to treat the enone with a reducing agent, preferablysodium hydrogen telluride in an alcoholic solvent such as methanol orethanol, and optionally in the presence of a mild buffer such asammonium chloride, until the starting material is consumed. Theprotected alcohol thus produced may be purified in the usual way, orused crude, and then the compound may be treated with hydrofluoric acidin aqueous acetonitrile to give the compound general formula IIa inwhich d is a single bond.

Compounds of general formula IIe may be prepared from compounds ofgeneral formula IIa by hydrolysis with a base such as lithium hydroxide,sodium hydroxide or potassium hydroxide in a mixture of water and anorganic solvent such as methanol, ethanol or tetrahydrofuran at atemperature between 0° C. and 50° C., preferably ambient temperature.The cation in compounds of general formula IIe is usually determined bythe cation of the hydroxide employed; however, the cation may then beexchanged for another cation by treatment with, for example,ion-exchange resins.

Compounds of general formula IIa may be used as intermediates in theproduction of compounds of general formulae IIb-e and of general formulaI as detailed in Scheme I, or they may be used as HMG-CoA reductaseinhibitors in their own right.

In compounds of general formulae I and II, the group R² may be modifiedto produce different compounds within the general formulae. Among themodifications that can be made are included reducing alkynes to alkenes,reducing alkenes to alkanes, isomerising between E and Z alkenes and/orremoving double and/or triple bonds once within the chain.

An enone of general formula XIV may be prepared from an aldehyde ofgeneral formula IXX by reaction with a phosphonate of general formulaXIII in which R¹¹ is a lower (e.g. C₁₋₈ or, preferably, C₁₋₄) alkylgroup such as methyl or ethyl, and the group P² is any group suitablefor the protection of hydroxyl groups, but preferably trialkylsilyl oralkyldiarylsilyl. The reaction between the aldehyde of general formulaXII and the phosphonate of general formula XIII may if convenient becarried out in either of the following two ways. In a first method thealdehyde of general formula XII and phosphonate of general formula XIIIare reacted together in the presence of a chelating metal halide such aslithium chloride or magnesium bromide and a mild organic base such astriethylamine or 1,8-diazabicyclo[4.5.0]undec-7-ene (DBU) in an inertsolvent such as acetonitrile or dimethyl sulphoxide at ambienttemperature. In a second method the phosphonate XIII is a first treatedwith a strong organic base such as lithium diisopropylamide or lithiumor sodium bis(trimethylsilyl)amide in an inert organic solvent such asdiethyl ether or tetrahydrofuran at a temperature between -78° C. and 0°C., the aldehyde of general formula XII added at the same temperature,and the mixture allowed to warm to ambient temperature, all under aninert atmosphere.

An aldehyde of general formula XII may be prepared from an alcohol ofgeneral formula X by oxidation, for example by conventional oxidationreagents such as pyridinium chlorochromate or pyridinium dichromate, orby using a catalytic quantity of tetra-n-propylammonium per-ruthenateand N-methylmorpholine N-oxide, in an inert organic solvent such asdichloromethane or tetrahydrofuran, but preferably the oxidation iscarried out using Swern's protocol.

An intermediate alcohol of general formula X may be prepared for examplein either of two ways from a diol of general formula VII. In the firstmethod the diol of general formula VII is acylated for example bytreatment with an excess of an acid anhydride ((R¹ CO)₂ O) or acidhalide (R¹ CO.Hal) in the presence of a catalyst such asN,N-dimethylaminopyridine, and a base such as triethylamine or pyridineuntil both hydroxyl groups in the compound of general formula VII havereacted. The diacylated compound of general formula XI is thenhydrolysed for example by treatment with an alkali metal hydroxide suchas lithium hydroxide, potassium hydroxide or sodium hydroxide in asolvent such as water or an alcohol, or a mixture of such solvents, at atemperature between 0° C. and ambient for a time suitable to maximise tothe production of the alcohol X.

In the second and preferred of the two exemplary methods, the diol ofgeneral formula VII is treated under conditions that will selectivelyprotect the primary alcohol, for example either as an ester or an ether.Such conditions are well known to one skilled in the art, but thepreferred conditions are to treat with one equivalent of atrialkylsilylchloride or alkyldiarylsilylchloride in the presence ofimidazole and, optionally, a mild organic base such as triethylamine orpyridine, and preferably using dichloromethane or chloroform as asolvent. The product of such a reaction will be a compound of generalformula VIII wherein P¹ is a trialkylsilyl or alkyldiarylsilyl moiety orother protective group. The compound of general formula VIII is thenacylated, for example using the conditions described above, that istreatment with the appropriate acid halide (R¹ CO.Hal) or preferably theanhydride ((R¹ CO)₂ O) using a mild organic base such as triethylamineor pyridine and optionally using a catalyst such asN,N-dimethylaminopyridine. The resulting intermediate, a compound ofgeneral formula IX, may then be deprotected to give an alcohol ofgeneral formula X using such conditions as are appropriate for theremoval of the group P¹, without affecting the rest of the molecule. Forthe removal of the preferred trialkylsilyl or alkyldiarylsilyl groups,the preferred methods are to use tetrabutylammonium fluoride in an inertsolvent such as tetrahydrofuran, or hydrofluoric acid in aqueousacetonitrile at ambient temperature. However, it will be appreciated byone skilled in the art that other methods are available for the removalof these preferred groups, or that other protecting groups may be usedin the transformation of a diol of general formula VII to an alcohol ofgeneral formula X.

Intermediate compounds of general formula XIV may also be synthesisedfrom the protected alcohols of general formula XV using the sequence ofreactions shown in Scheme III, in which R², R⁴, R⁵, R¹¹ and P² are aspreviously defined, and P³ is defined below.

An intermediate of general formula XIV may be prepared from an enone ofgeneral formula XVIII by acylation, for example using conventionalmeans. Thus, a compound of general formula XIV may be prepared bytreating an alcohol of general formula XVIII with an acid chloride orbromide (R¹ CO.Hal), or preferably an anhydride ((R¹ CO)₂ O) in thepresence of a mild organic base such as pyridine or triethylamine, andpreferably using a catalyst such as N,N-dimethylaminopyridine, eitherneat or in an inert solvent, preferably dichloromethane or chloroform ata temperature between 0° C. and reflux. Alternatively the transformationmay be carried out using the acid (R¹ CO₂ H) and a coupling reagent suchas a carbodiimide and a catalyst such as N,N-dimethylaminopyridine, inan inert solvent and preferably at ambient temperature.

An enone of general formula XVIII may be prepared from an aldehyde ofgeneral formula XVII and a phosphonate of general formula XIII asdefined above for example by using a chelating metal halide such aslithium chloride or magnesium bromide and a mild organic base such astriethylamine or DBU in an inert organic solvent, preferablyacetonitrile or dimethylsulphoxide, at a temperature from 0° C. toambient and preferably under an inert atmosphere.

To prepare an aldehyde of general formula XVII, an alcohol of generalformula XV, in which the group P³ is any group suitable for theprotection of alcohols, (preferably trialkylsilyl or alkyldiarylsilyl)may be oxidised to an aldehyde of general formula XVI for example byconventional means such as pyridinium chlorochromate or pyridiniumdichromate, or by using a catalytic quantity of tetra-n-propylammoniumper-ruthenate (TPAP) in the presence of N-methylmorpholine N-oxide in aninert solvent, preferably dichloromethane, but most preferably by usingSwern's protocol. The protecting group P³ may then be removed by anyappropriate method (but in the preferred case where P³ is trialkylsilyor alkyldiarylsilyl, the group may be removed by any method thatgenerates fluoride ions, and preferably using hydrofluoric acid inaqueous acetonitrile, at ambient temperature under an inert atmosphere)to give a hydroxy aldehyde of general formula XVII.

Intermediate alcohols of general formulae VII and XV useful in thesyntheses outlined in Schemes II and III may be prepared as shown inScheme IV, in which R², R⁵ and P³ are as previously defined, R¹⁰ islower alkyl, and R⁹ is as defined below.

An intermediate alcohol of general formula XV may be prepared byreduction of the ester group in a compound of general formula XXI, forexample using conventional reagents such as lithium aluminum hydride,diisobutylaluminium hydride or lithium triethylborohydride in an inertorganic solvent such as diethyl ether or tetrahydrofuran, at ambienttemperature to reflux, under an inert atmosphere. The alcohol of generalformula XI may be then be used as outlined in Scheme III or may bedeprotected to give an alcohol of general formula VII, which may then beused as in Scheme II. The deprotection may be carried out by any meanssuitable for removal of the group P³, but in the preferred cases inwhich the group P³ is a trialkylsilyl or alkyldiarylsilyl group, thereaction is preferably carried out using hydrofluoric acid in aqueousacetonitrile, at ambient temperature.

Alternatively, an alcohol of general formula VII may be prepared from anester of general formula XXI by firstly removing the protecting group P³and then reducing the ester group in the compound of general formulaXXII so formed to the alcohol. The deprotection of a compound of generalformula XXI to give a compound of general formula XXII may be carriedout in a manner similar to the deprotection of an alcohol of generalformula XV, in cases where P³ is one of the preferred groups bytreatment with hydrofluoric acid in aqueous acetonitrile, and thereduction of a compound of general formula XXII to a compound of generalformula VII may be carried out in a similar manner to the reduction ofan ester of general formula XXI to an alcohol of general formula XV byusing a (for example conventional) reducing agent in an inert solventsuch as diethyl ether or tetrahydrofuran. It is within the capabilitiesof one of ordinary skill in the art to select the best alternative ofthose detailed above, according to the exact nature of the groups R¹⁰and P³.

An intermediate of general formula XXI may be prepared from an aldehydeof general formula XX by reaction with an ylid of general formula XXVIIIin which R⁹ is C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, or C₁₋₃ alkyl,alkenyl, or alkynyl substituted with substituted phenyl, in an inertorganic solvent, preferably tetrahydrofuran, at a temperature between-78° C. and ambient. It should be appreciated by those skilled in theart that the exact combination of reaction conditions such as solvent,temperature, and reagents used may be varied to produce predominantlyone isomer about the newly formed double bond. For example, generationof the ylid by treating ethyl triphenylphosphonium bromide with sodiumbis(trimethylsilyl)amide in tetrahydrofuran, at -78° C., then additionof the aldehyde and allowing the mixture to warm to ambient temperaturegives a compound in which the newly created alkene is entirely cis--CH═CHMe. However, if the ylid is generated using lithiumbis(trimethylsilyl)amide, then a mixture of cis and trans isomers isobtained. This mixture may be carried through the synthetic sequencedescribed above to give a mixture of compound of general formula I orII, or, preferably, separated using standard techniques and theindividual components utilised according to the schemes.

An aldehyde of general formula XX may also be used to introduceacetylenic unsaturation into the group R² in compounds of the invention.For example, any of the following schemes may be appropriate: ##STR8##

The acetylene R--C═CH can then be deprotonated and substituted with anappropriate electrophilic radical. Scheme (c) is preferred, usinglithium amalgam, as a strong base is not required under theseconditions.

Acetylenes may also be produced by reacting a compound of generalformula XXII (R--HC═CH--R') with Br₂ /CCl₄ and then with NaNH₂ in NH₃ orDMSO to form a compound of the general formula R--HC═CH--R', which maysubsequently be used as a compound of general formula XXII, althoughreaction conditions should be selected appropriately to avoid unwantedeffects on the ring double bond.

An aldehyde of general formula XX may be prepared from an alcohol ofgeneral formula XIX by oxidation, for example using conventionalreagents such as pyridinium dichromate or pyridinium chlorochromate, orby using a catalytic quantity or tetra-n-propylammonium per-ruthenate(TPAP) in the presence of N-methylmorpholine N-oxide, in an inertorganic solvent, preferably dichloromethane or chloroform at atemperature between 0° C. and ambient; the transformation is mostpreferably achieved by using Swern's protocol.

Intermediate esters of general formula XXII may also be produced by thereactions outlined in Scheme V, in which R⁵, R⁹, and R¹⁰ are as definedpreviously, and R¹² is defined below.

An alcohol of general formula XXV may be reduced to an intermediate ofgeneral formula XXII for example by treatment with sodium amalgam in analcohol such as methanol or ethanol, and preferably buffered using aphosphate salt such as dipotassium (or disodium) hydrogen phosphate.

Alternatively, an alcohol or general formula XXV may be acylated forexample with an acid anhydride ((R¹² CO)₂ O) or acyl halide (R¹² CO.Hal)and a mild organic base such as pyridine or triethylamine, andpreferably using N,N-dimethylaminopyridine as a catalyst, in an inertsolvent, preferably dichloromethane or chloroform, to give anintermediate ester of general formula XXVI in which R¹² may be C₁₋₅alkyl, fluorinated C₁₋₅ alkyl, or substituted phenyl, but is preferablymethyl, ethyl or phenyl. The acylated compound of general formula XXVImay then be transformed to an alcohol of general formula XXII in thesame way that a compound of general formula XXV may be transformed asdiscussed above, that is for example by treatment with sodium amalgam ina buffered alcoholic solvent.

A keto-sulphone of general formula XXIV may be produced from a lactoneof general formula XXIII by reaction with an anion or dianion of asulphone of general formula XXVII, in an inert organic solvent,preferably tetrahydrofuran, at -78° C. to ambient temperature under aninert atmosphere. Reduction of the ketone group in a compound of generalformula XXIV, which may be carried out using conventional reagents suchas sodium borohydride, cerium borohydride, lithium triethylborohydride,or lithium aluminum hydride in an inert organic solvent from 0° C. toambient temperature, and preferably using sodium borohydride in methanolor ethanol at ambient temperature, then gives an alcohol of generalformula XXV. The alcohol of general formula XXV thus produced is amixture of diastereoisomers which may be used as a mixture, or separatedand used individually.

It will be apparent to one skilled in the art that the exact combinationof reaction conditions and reagents used may be varied to producedpredominantly one isomer about the newly formed double bond. Forexample, in the case in which R⁹ is methyl, elimination of the alcoholof general formula XXV gave material in which the trans:cis ratio aboutthe new double bond was approximately 6:1. It is within the capabilitiesof one skilled in the art to select conditions, and to choose betweenthe routes outlined in Schemes IV and V, in order to maximise theproduction of the desired isomer of esters of general formula XXII.Esters of general formula XXII may then be used to produce compounds ofgeneral formulae I or II as detailed in Schemes I to III.

Keto-sulphones of general formula XXIV may also be used to introduceacetylenic unsaturation by reaction first with (EtO)₂ P(O)Cl and a mildbase and then reduction with sodium amalgam to produce the acetyleneanalogue of a compound of general formula XXII (R--HC═CH--R'). Thisconstitutes a preferred method of synthesis of acetylenes as it avoidsthe need for a strong base.

Another method of obtaining the intermediate esters of general formulaXXI is outlined in Scheme VI in which R⁵, R¹⁰, and P³ are as previouslydefined, and R⁸ and L are defined below.

An ester of general formula XXI may be obtained by treating anintermediate of general formula XXIX in which L represents a leavinggroup such as tosyl, mesyl, trifluoromethylsulphonyl, or halide(particularly iodide) with an organometallic reagent that will deliverthe group R⁸ (where R⁸ is hydrogen, C₁₋₇ alkyl, C₁₋₇ alkenyl, C₁₋₇alkynyl, or C₁₋₄ alkyl, alkenyl, or alkynyl substituted with substitutedphenyl) in such a manner that it may be formally represented as acarbanion, in an inert solvent such as diethyl ether or tetrahydrofuran,at a temperature between -78° C. and reflux, under an inert atmosphere.

Examples of suitable organometallic reagents are lithiumtriethylborohydride, methyl lithium, phenyl lithium, methyl magnesiumbromide, lithium acetylide, vinyl lithium, dimethyl copper lithium orother higher order or lower order cooper reagents. The exact form of theorganometalic reagent used depends on the form of the leaving grippresent in general formula XXIX, and on the other functionality presentin the group R⁸.

Alternatively, in the case where R⁸ represents hydrogen, the compound ofgeneral formula XXI may be obtained from a compound of general formulaXXIX in which L represents iodide by treatment with a hydrogen radicalsource, for example tributyl tin hydride in an inert solvent such asbenzene or toluene.

An intermediate of general formula XXIX may be prepared from an alcoholof general formula XIX for example using conventional, well-knownprocedures.

Compounds of general formula I in which R⁵ is methyl may also beobtained from known compounds of general formulae LXX and LXXI(EP-A-0251625), using the methods outlined in reaction Scheme VII inwhich R¹, R²,and L are as previously defined.

Lactones of general formula I may be obtained from the protectedlactones of general formula LXXIII preferably by treatment withtetrabutylammonium fluoride in tetrahydrofuran buffered with acetic acidat ambient temperature.

A lactone of general formula LXXIII may be obtained by treating anintermediate of general formula LXXII with an organometallic, preferablyorganocopper, reagent that will deliver the group R⁸ (as previouslydefined) in such a manner that it may be formally represented as acarbanion, for example, dimethyl copper lithium or other higher order orlower order copper reagents, in an inert solvent such as diethyl etheror tetrahydrofuran, at a temperature between -78° C. and ambient, underan inert atmosphere. The exact form of the organometalic reagent useddepends on the form of the leaving group present in general formulaLXXII, and on the other functionality present in the group R⁸.

An intermediate of the general formula LXXIII may also be prepared froman aldehyde of the general formula aldehyde LXXI by reaction with anylid of general formula XXVIII, as defined previously, in an inertorganic solvent, preferably tetrahydrofuran, at a temperature between-78° C. and ambient. It should be appreciated by those skilled in theart that the exact combination of reaction conditions such as solvent,temperature, and reagents used may be varied to produce predominantlyone isomer about the newly formed double bond in the group R². Anymixture of double bond isomers may be carried through the syntheticsequence to give compounds of general formula I or II, or (preferably)separated using standard techniques and the individual componentsutilised according to the schemes.

An intermediate of general formula LXXII may be prepared from an alcoholof general formula LXX for example using conventional, well-knownprocedures.

Intermediates of general formulae XIX and XXIII in which R⁵ is methyl,R¹⁰ is ethyl and P³ is a t-butyldimethylsilyl group, a and b are bothsingle bonds and c is a double bond, are known in the literature (J.Chem. Soc., Chem. Commun., 1987, 1986). Those intermediates in which R⁵,R¹⁰ and P³ are other groups within the appropriate definitions may beprepared using routes analogous to the known route, but using theappropriately different starting materials. Such a change is within thescope of one skilled in the art. Methods for the introduction of asecond double bond at a, isomerising to give a single double bond at aor b, or reducing to give a, b and c as single bonds in compounds withstructures similar to the compounds of general formulae I, II, IV, V,VII to XII, XIV to XXIX and LXX to LXXIII are known in the art (forexamples, see Tetrahedron 1986, 42, 4909-4951 or U.S. Pat. No.4,293,496). Some of these methods may use reagents that under certainconditions deleteriously affect at least some of compounds of generalformulae I, II, IV, V, VI to XII, XIV to XXIX and LXX to LXXIII;however, other methods may be suitable for the required transformationsin some or all of the compounds of general formulae I, II, IV, V, VII orXII, XIV to XXIX and LXX to LXXIII. Thus it is within the capabilitiesof one skilled in the art to select appropriate methodology for theinterconversion of compounds wherein a, b and c may be single or doublebonds (subject to the restrictions mentioned in the description), inorder to obtain compounds of general formula I or II with the requiredsingle or double bonds at a, b or c.

A phosphonate of general formula XIII in which R⁴ and R¹¹ are methyl andP² is a t-butyldimethylsilyl group is known in the art (J. Org. Chem.,1988, 53, 2374-2378). Compounds of general formulae XXVII and XXVIII arecommercially available or are readily available from commerciallyavailable materials using known or analogous methods.

In general, reagents are used in sufficient quantities completely toconvert starting materials to products but to be themselvessubstantially consumed during the course of the reaction. However theamounts may often be varied as is evident to one of ordinary skill inthe art. For example, in a reaction of two compounds one of which is notreadily available and one of which is, an excess of the readilyavailable compound may be used to drive the reaction further towardscompletion (unless the use of an excess would increase the synthesis ofan undesired compound).

Likewise, most of the temperature ranges given in the precedingdescriptions are merely exemplary, and it is within the ability of oneof ordinary skill int he art to vary those that are not critical.

The reaction times set forth in the preceding description are alsomerely exemplary and may be varied. As is well-known, the reaction timeis often inversely related to the reaction temperature.

Generally, each reaction is monitored, for example by thin layerchromatography, and is terminated when at least one starting material isno longer detectably present, or when it appears that no more of thedesired product is being formed.

Conventional work-up procedures have generally been omitted from thepreceding descriptions.

As utilised in the preceding descriptions, the term "solvent" embracesmixtures of solvents and implies that the reaction medium is a liquid atthe desired reaction temperature. It should, therefore, be understoodthat not all of the solvents listed for a particular reaction may beutilised for the entire cited temperature range. It should also beunderstood that the solvent must be at least substantially inert to thereactants employed, intermediates generated and end products under thereaction conditions utilised.

The term "inert atmosphere", as utilised in the preceding descriptions,means an atmosphere that does not react with any of the reactants,intermediates or end products or otherwise interfere with the reaction.While a carbon dioxide atmosphere is suitable for certain reactions, theinert atmosphere is usually nitrogen, helium, neon, or argon, or amixture thereof, and most often dry argon to maintain anhydrousconditions. Most reactions, including those where the use of an inertatmosphere is not specified, are carried out under an inert atmosphere,usually dry argon, for convenience.

The product of each reaction may, if desired, be purified byconventional techniques such as recyrstalisation (if a solid), columnchromatography, preparative thin lay chromatography, gas chromatography(if sufficiently volatile), fractional distillation under high vacuum(if sufficiently volatile) or high pressure (performance) liquidchromatography (HPLC). Often, however, the crude product of one reactionmay be employed in the following reaction without purification or evenwithout isolation.

Some reactions, particularly those utilising strong bases or reducingagents, require anhydrous solvents. Where this is the case solvents maybe dried before use using conventional techniques and an inertatmosphere used.

Some of the reactions described above may yield mixtures of two or moreproducts, only one of which leads to the desired compound of generalformula I or II. Any mixture so obtained may be separated byconventional techniques such as those set forth in the precedingparagraphs.

Certain of the intermediate compounds described above are believed to benoel, in particular compounds of general formulae IV, XIV and LXXIII.All other intermediate comounds in which either or both of R² and R⁵ arenot methyl are also believed to be novel.

Compounds of this invention are useful as antihypercholesterolaemicagents for the treatment of arteriosclerosis, hyperlipidaemia, familialhypercholesterolaemia and the like diseases in humans.

According to a third aspect of the invention, there is thereforeprovided a compound of general formula I or II for use in medicine,particularly as antihypercholesterolaemic agents.

According to a fourth aspect of the invention, there is provided the useof a compound of general formula I or II in the preparation of anantihypercholesterolaemic agent. Compounds of the invention cantherefore be used in a method for the treatment of prophylaxis ofhypercholesterolaemia in general and arteriosclerosis, familialhypercholesterolaemia or hyperlipidaemia in particular comprisingadministering to a patient an effective dose of a compound of generalformula I or II or a mixture thereof.

According to a fifth aspect of the invention, there is provided apharmaceutical composition comprising a compound of general formula I orII, or a mixture thereof, and a pharmaceutically acceptable carriertherefor. Such a composition may simply be prepared by the admixture ofthe ingredients.

Compounds of general formula I and II may be administered orally orrectally or parenterally in the form of a capsule, a tablet, aninjectable preparation of the like. It is usually desirable to use theoral route. Doses may be varied, depending on the age, severity, bodyweight and other conditions of human patients but daily dosage foradults is within a range of from about 2 mg to 2000 mg (preferably 5 to100 mg) which may be given in one to four divided doses. Higher dosesmay be favourably employed as required.

The compounds of this invention may also be co-administered withpharmaceutically acceptable nontoxic cationic polymers capable ofbinding bile acids in a non-reabsorbable form in the gastrointestinaltract. Examples of such polymers include cholestyramine, colestipol andpoly[methyl-(3-trimethylamino-propyl)iminotrimethylene dihalide]. Therelative amounts of the compounds of this invention and these polymersis between 1:100 and 1:15000.

The intrinsic HMG-CoA reductase inhibition activity of the claimedcompounds may be measured in in vitro protocols described in detail inthe Examples below.

Included within the scope of this invention is the method of treatingarteriosclerosis, familial hypercholesterolaemia or hyperlipidaemiawhich comprise administering to a subject in need of such treatment anontoxic therapeutically effective amount of the compounds of Formulae Ior II or pharmaceutical compositions thereof.

Compounds of general formula IV may also show HMG-CoA reductaseinhibition activity and so may be included in the pharmaceutical aspectsof the invention.

The following examples show representative compounds encompassed by thisinvention and their syntheses. However, it should be understood thatthey are for the purposes of illustration only.

Organic solutions were dried over sodium sulphate or magnesium sulphate,and evaporated under reduced pressure. NMR spectra were recorded atambient temperature in deuteriochloroform at 250 MHz for proton and 62.5MHz for carbon unless noted otherwise. All chemical shifts are given inparts per million relative to tetramethylsilane. Infra red spectra wererecorded at ambient temperature in solution in chloroform, or in thesolid state in a potassium bromide disc as noted.

Chromatography was carried out using Woelm 32-60 μm silica.

EXAMPLE 1 Compound J

Methyl (1S,2S,4aR,6S,8S,8aS,3'R,2"S)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3'-hydroxy-5'-oxoheptanoate##STR9##

Step 1

Ethyl (1S,2S,4aR,2S,8S,8aS)-1,2,4a,5,6,8,8a-octahydro-8-hydroxy-6-(1-hydroxy-2-(phenylsulphonyl)propyl)-2-methyl-naphthalene-1carboxylate (XXV)

Ethyl phenylsulphone (General Formula XXVII, R⁹ =methyl; 2.6 g, 15.2mmol) was dissolved in dry tetrahydrofuran (THF) (100 mL) and cooled to-78° C., under argon. n-Butyl-lithium (1.4 M solution in hexane; 11 mL,15.4 mmole) was added and stirring continued for 30 minutes at -78° C. Asolution of (+) ethyl (1S,2S,4aR,6S,8S,8aS)-1,2,4a,5,6,8,8a-octahydro-2-methyl-6,8-naphthalene-carbolactone-1-carboxylate(general formula XXIII, R⁵ =methyl; 2.00 g, 7.6 mmole) in dry THF (80mL) was added to the reaction mixture over 45 minutes, the solutionstirred for a further 2 hours, then the reaction quenched by addition ofammonium chloride solution (50 mL). The mixture was warmed to roomtemperature, poured into either (100 mL), and the remaining soliddissolved using the minimum amount of water. The two phases wereseparated and the organic phase was washed with ammonium chloridesolution (100 mL) and brine (100 mL). The organic solution was dried andevaporated to give a crude oil which was used in the next stage withoutfurther purification.

Sodium borohydride (0.15 g, 3.96 mmole) was added to a solution of thecrude sulphone addition product in ethanol (100 mL), under argon, themixture stirred overnight, quenched by the addition of water (100 mL),then extracted into ether (100 mL). The two phases were separated andthe organic phase washed with brine (2×100 mL). The combined aqueoussolutions were extracted with ether (100 mL), which was then washed withmore brine (100 mL). The combined organic solutions were dried andevaporated to an orange oil. Chromatography eluting with 9:1hexane:ethyl acetate then 4:1 hexane:ethyl acetate gave the pure alcohol(XXV; 1.07 g, 32%) as a colourless oil.

delta H 7.95-7.5 (5H, m), 5.52 (1H, ddd, J 10, 4 and Hz), 5.40 (1H, d, J10 Hz), 4.57 (1H, dd, J 10 and 1 Hz), 4.0-4.2 (3H, m), 3.49 (1H, dq, J 6and 1 Hz), 2.7-2.6 (2H, m), 2.28 (1H, br t, J 13 Hz), 2.14 (1H, br d, J14 Hz), 2.9-2.8 (1H, br m), 1.65-1.6 (3H, m), 1.45 (1H, td, J 111 and 2Hz), 1.33 (3H, d, J 7 Hz), 1.26 (5H, t, J 7 Hz), and 0.92 (3H, d, J 7Hz)

Step 2

Ethyl (1S,2S,4aR,6S,8S,8aS)-1,2,4a,5,6,8,8a-octahydro-8-hydroxy-2-methyl-6-((E)-prop-1-enyl)naphthalene-1-carboxylate(XXII)

Di-sodium hydrogen phosphate (8.6 g, 0.06 mmole) and freshly prepared 6%sodium amalgam (17.25 g) were added to a solution of the alcohol fromthe previous step (1.07 g, 2.45 mmole) in ethanol (75 mL), under argon,and stirring continued overnight at room temperature. The organics weredecanted off and the amalgam and phosphate buffer washed with ether(2×50 mL). The combined organics were washed with water (2×50 mL), driedand evaporated to give a solid which was purified by chromatographyusing 9:1 hexane:ethyl acetate as eluent to give the olefin (0.12 g,18%) as an off-white solid.

delta H 5.84 (1H, dd, J 15 and 6 Hz), 5.6-5.5 (2H, m), 5.42 (1H, d, J 10Hz), 4.29 (1H, m), 4.14 (2H, q, J 7 Hz), 2.84 (1H, dd, J 11 and 6 Hz),2.7-2.5 (2H, m), 2.40 (1H, br t, J 13 Hz), 2.00 (1H, dq, J 15 and 3 Hz),1.9-1.7 (2H,m), 1.68 (3H, d, J 6.5 Hz), 1.50 (1H, td, J 13 and 3 Hz),1.38 (1H, td, J 13 and 5 Hz), 1.26 (3H, t, J 7 Hz), and 0.93 (3H, d, J 7Hz)

Step 3

(1S,2S,4aR,6S,8S,8aS-1,2,4a,5,6,7,8,8a-octahydro-8-hydroxy-1-hydroxymethyl-2-methyl-6-((E)-prop-1-enyl)-naphthalene(VII)

A solution of the ester from the previous step (0.60 g, 2.16 mmole) indry diethyl ether (5 mL) was added dropwise to a stirred suspension oflithium aluminium hydride (0.25 g, 6.48 mmol) in dry diethyl ether (5mL) under argon. After two hours, the suspension was cooled in an icebath and water (0.25 mL) was added dropwise, followed by sodiumhydroxide solution (15%, 0.25 mL) and water (0.75 mL). The mixture wasfiltered, the solid washed with diethyl ether and the organicsevaporated under reduced pressure to leave the crude diol (0.52 g) as anoil which was used without purification in the next step. delta H 5.93(1H, ddd, J 14.5, 6.5, and 1.5 Hz), 5.6-5.5 (2H, m), 5.39 (1H, d, J 9.5Hz), 4.2 (1H, brs), 3.75 (1H, d, J 8.5 Hz), 3.7-3.5 (1H, dd, J 8.5 and 3Hz), 2.85-2.6 (2H, br m), 2.3-2.6 (3H, br m), 2.1-1.7 (4H, m), 1.68 (3H,dt, J 6.5, and 1 Hz), 1.33 (1H, td, J 13 and 6 Hz),1.22 (1H, td, J 11.5and 1 Hz), and 0.82 (3H, d, J 6.5 Hz)

Step 4

(1S,2S,4aR,6S,8S,8aS)-1-(t-butyldimethylsilyl)oxymethyl-1,2,4a,5,6,7,8,8a-octahydro-8-hydroxy-2-methyl-6-((E)-prop-1-enyl)naphthalene (VIII)

t-Butyldimethylsilyl chloride (0.358 g, 2.37 mmole) was added inportions to a stirred solution of the diol from the previous step (0.52g, 2.16 mmole) and imidazole (0.161 g, 2.37 mmole) in drydichloromethane (5 mL). The mixture was stirred for 18 hours thenpartitioned between dichloromethane (20 mL) and 1M H₃ PO₄ (5 mL). Theorganic phase was separated and washed successively with water (10 mL),saturated sodium bicarbonate solution (10 mL) and brine (7 mL) thendried and evaporate to leave a gum, which was purified by columnchromatography eluting with hexane, then hexane:ethyl acetate (9:1) togive the monosilyl ether as a gum (0.62 g, 82%).

delta H (key peaks) 3.55 (1H, t, J 9 Hz, CH_(A) H_(B) OSi), 3.50 (1H,dd, J 9 and 2.5 Hz, CH_(A) H_(B) OSi), 0.91 (9H, s, C(CH₃)₃), and 0.1(6H, s, Si(CH₃)₂)

Step 5

(1S,2S,4aR,6S,8S,8aS,2'S)-1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8[(2'-methyl-1'-oxobutyl)oxy]-6-[(E)-prop-1-enyl]naphthalene-1-carbaldehyde(XII)

2(S)-methylbutyric anhydride (1.0 g, 5.37 mmole), dry pyridine (1.3 mL,16.2 mmole) and 4-dimethylaminopyridine (DMAP; 16 mg, 0.13 mmole) wereadded to a solution of alcohol from the previous step (0.315 g, 0.9mmole) in dry dichloromethane (1.5 mL) and the solution heated to 60° C.for 19 hours under argon. The mixture was cooled, diluted with methanol(8.0 mL) and stirred for 1 hour, then partitioned between diethyl ether(80 mL) and 1M H₃ PO₄ (10 mL). The organic phase was separated andwashed successively with H₃ PO₄ (10 mL), water (10 mL), saturated sodiumbicarbonate solution (15 mL) and brine (10 mL), then dried andevaporated to give the acylated product (IX) as a yellow gum, (0.48 g),which was of sufficient purity to proceed directly with the next stage.

delta H (key peaks) 5.0 (1H, m, 8-H), 2.33 (1H, sextet, J 7 Hz, CHCO.O),1.15 (3H, d, J 7 Hz, CH₃ CH), 0.9 (3H, t, J 7 Hz, CH₃ CH₂), 0.85 (9H,s), 0.1 (3H, s), and -0.1 (3H, s)

A solution of the silylated ester (IX) prepared above (0.48 g, 1.11mmole) in 40% aqueous HF:acetonitrile (1:19) (8.5 mL) was stirred forhalf an hour, then saturated sodium bicarbonate solution (10 mL) anddiethyl ether (50 mL) added, the aqueous phase separated and furtherextracted with ether (50 mL). The combined organic layers were washedwith brine (20 mL), dried and evaporated to leave the alcohol (X) as agum, (330 mg), which was used directly in the next stage.

A solution of dry DMSO (0.20 g, 2.55 mmole) in dry dichloromethane (0.8mL) was added slowly to a cold (-70° C.), stirred solution of oxalylchloride (0.162 g, 1.27 mmole) in dry dichloromethane (2.0 mL) under anargon atmosphere. After 5 minutes, a solution of the alcohol (X) (0.32g, 1.03 mmole) in dry dichloromethane (2.0 mL) was added dropwise,stirred for 10 minutes, then a second batch of the DMSO/COCl₂ complex(formed as above; 1.27 mmole) was added dropwise. The solution wasstirred for 10 minutes, triethylamine (1.3 mL, 9.26 mmole) addeddropwise and the mixture allowed to warm to room temperature. After 1hour, the mixture was diluted with diethyl ether (50 mL), washed with 1MH₃ PO₄ (20 mL), water (3×20 mL, saturated sodium bicarbonate solution(2×20 mL), brine (20 mL) and then dried. Evaporation gave the crudealdehyde which was purified by column chromatography eluting with ethylacetate:hexane (1:20), giving the aldehyde (XII) (195 mg, 56% from thediol VII).

delta H (key peaks) 9.68 (1H, d, J 2 Hz, CHO), 5.3 (1H, m, 8-H), and2.65 (1H, m, 1-H)

Step 6

Methyl (1S,2S,4aR,6S,8S,8aS,3'R,2"S)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3'-t-butyldimethylsilyloxy-5'-oxohept-6'-enoate(XIV)

A solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0M,0.39 mmole) was added dropwise to a cold (-70° C.) stirred solution ofmethyl 3(R)(t-butyldimethylsilyloxy)-5-oxo-6-(dimethylphosphonyl)hexanoate (general formula XIII; 172 mg, 0.45 mmole) in THF (0.3 mL)under argon. After 1 hour, a solution of aldehyde (XII) (95.4 mg, 0.3mmole) in THF (0.3 mL) was added, the solution allowed to warm to roomtemperature and stirred for 64 hours. The reaction was quenched withsaturated ammonium chloride solution (5 mL) and extracted withdichloromethane (3×10 mL), which was dried and evaporated to leave agum. Purification by column chromatography eluting with ethylacetate:hexane (1:25) to ethyl acetate:hexane (1:20), gave the enone(XIV) (82 mg, 66% based on recovered aldehyde XII).

delta H (key peaks) 6.75 (1H, dd, J 16 and 10 Hz, 7'-H), 5.97 (1H, d, J16 Hz, 6'-H), 4.59 (1H, quintet, J 6 Hz, 3'-H), 3.64 (3H, s, OCH₃), 2.81(1H, dd, J 16 and 6 Hz), 2.71 (1H, dd, J 16 and 6 Hz), 2.54 (1H, dd, J14 and 5 Hz), 2.44 (1H, dd, J 14 and 6 Hz), 0.82 (9H, s), 0.05 (3H, s),and 0.02 (3H, s).

Step 7

Methyl (1S,2S,4aR,6S,8S,8aS,3'R,2"S)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3'-hydroxy-5'-oxoheptanoate(IIa)

A solution of chlorotris(triphenylphosphine) rhodium (I) (2.6 mg, 2.85micromole) and the enone, (82 mg, 143 mmole) in triethylsilane (2.85 mL,18.5 mmole) was heated to 50° C. with stirring, under argon, for 1.5hours. The solvent was evaporated, the residue dissolved in a solutionof 40% aqueous hydrofluoric acid in acetonitrile (1:20; 10 mL) and themixture stirred for 1 hour under argon. Ethyl acetate (20 mL) was addedand the organic phase washed with saturated sodium bicarbonate solution(10 mL), which was re-extracted with ethyl acetate (10 mL). The combinedethyl acetate extracts were washed with brine (10 mL), dried andevaporated to leave a gum which was purified by column chromatographyeluting with ethyl acetate:hexane (1:4), giving the ketone (45 mg, 69%)as a gum.

delta H 5.72 (1H, dd, J 15 and 8 Hz), 5.6 (1H, m), 5.35 (1H, br d, J 9Hz), 5.25 (1H, m), 5.15 (1H, m), 4.40 (1H, m), 3.69 (3H, s), 3.39 (1H,br d, J 3 Hz), 2.58 (2H, d, J 5 Hz), 2.48 (2H, d, J 6 Hz), 2.45-1.13(16H, m), 1.59 (3H, br d, J 6 Hz), 1.11 (3H, d, J 7 Hz), 0.9-0.79 (6H,m)

EXAMPLE 2 Compound H

Methyl(1S,2S,4aR,6S,8S,8aS,3'R,5'R,2"S)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3',5'-dihydroxyheptanoate##STR10##

A solution of triethylborane (1.0 M in THF; in 0.1 mmole) was added to astirred solution of MeOH (0.2 mL) in THF (0.8 mL) under argon. After 45minutes, 0.22 mL of this mixture was cooled to -70° C., a solution ofthe ketone of Example 1 (compound J) (8.1 mg, 0.017 mmole) in THF:MeOH(4:1) was added dropwise and stirred a further 1.75 hours. Sodiumborohydride (1.0 mg, 0.26 mmole) was added rapidly under argon, thesolution stirred for 2.5 hours, then warmed to room temperature andquenched with saturated ammonium chloride solution (0.5 mL). The mixturewas stirred for 15 minutes, extracted with ethyl acetate (2×5 mL), driedand evaporated to a gum. Chromatography eluting with hexane:ethylacetate (3:2) gave the diol as a colourless oil (5.0 mg, 62%).

delta H 0.83 (3H, d, J 7 Hz), 0.91 (3H, t, J 7 Hz), 1.1-2.1 (23H, m),2.3 (2H, m), 2.5 (3H, d+m, J 7 Hz), 3.27 (1H, br s), 3.71 (3H, s), 3.80(1H, m), 4.25 (1H, m), 5.20 (1H, m), 5.37 (1H, br d, J 10 Hz), 5.4 (1H,m), 5.65 (1H, ddd, J 10, 5 and 3 Hz), 5.75 (1H, dd, J 14 and 7 Hz)

EXAMPLE 3 Compound G

(1S,2S,4aR,6S,8S,8aS,4'R,6'R,2"S)6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8[(2"-methyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one##STR11##

A mixture of the diol of example 2 (compound H) (40 mg) and tosic acid(14 mg, 0.074 mmole) in dry benzene (6 mL) was stirred for half an hour,evaporated, then azeotroped again with benzene (1 mL). The residue wastaken up in benzene (5 mL), treated again with tosic acid (14 mg, 0.074mmole), stirred for half an hour, evaporated under reduced pressure andthe residue purified by column chromatography eluting with ethylacetate:hexane (2:5) to give the lactone as a gum (4.7 mg).

delta H 5.8-5.6 (2H, m), 5.45-5.35 (2H, m), 5.19 (1H, m), 4.65 (1H, m),4.37 (1H, m), 2.73 (1H, dd, J 17 and 5 Hz), 2.64 (1H, ddd, J 17, 4, and1 Hz), 2.50 (1H, br m), 2.32 (3H, br m), 2.1-1.2 (18H, m), 1.12 (3H, d,J 7 Hz), and 0.95-0.81 (6H, m)

delta C 176.1, 170.0, 135.9, 132.5, 130.8, 123.0, 76.0, 69.3, 69.2,62.6, 41.7, 41.6, 38.5, 37.3, 36.0, 35.9, 35.2, 32.9, 31.5, 31.3, 26.6,23.0, 17.9, 16.3, 14.8, 11.7

EXAMPLE 4 Compound M

Methyl (1S,2S,4aR,6S,8S,8aS,3'R)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3'-hydroxy-5'-oxoheptanoate##STR12##

The compound was prepared in the same manner as the compound of Example1 (compound J) but substituting 2,2-dimethylbutyryl chloride for(S)-2-methylbutyric anhydride in step 5. In addition the procedure ofstep 7 for the reduction and deprotection of the enone was replaced bythe following procedure.

A solution of methyl (1S,2S,4aR,6S,8S,8aS,3'R)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3'-t-butyldimethylsilyloxy-5'-oxohept-6'-enoate(general formula XIV) (66 mg, 0.12 mmol) and ammonium chloride (179 mg,3.4 mmol) was stirred at room temperature under argon, and sodiumhydrogen telluride solution (0.21M in ethanol, 1.6 mL, 0.34 mmol) wasadded. Further quantities of the telluride were added after 30 minutes(1.4 mL) and 1 hour (0.5 mL). After stirring for a further 20 minutesthe solvent was evaporated and the residue partitioned betweendichloromethane (50 mL) and saturated ammonium chloride solution (10mL). The organic layer was dried and the solvent evaporated to leave aclear oil (66 mg).

The oil was taken up in 5 mL of 19.1 acetonitrile:aqueous hydrofluoricacid (40%), the mixture stirred for 45 minutes at room temperature, thendiluted with ethyl acetate (25 mL). After washing with saturated aqueoussodium bicarbonate solution (10 mL) and brine (10 mL), the organicsolution was dried and evaporated to leave a yellow oil, which waspurified by chromatography eluting with hexane:ethyl acetate (9:1 to4:1) to leave the alcohol as a white solid (49 mg, 88%).

delta H 0.75-0.9 (6H, m), 1.1-1.45 (10H, m), 1.5-1.85 (10H, m), 2.02(1H, d, J 15 Hz), 2.1-2.3 (2H, m), 2.4-2.5 (3H, m), 2.50 (2H, d, J 6Hz), 3.38 (1H, d, J 4 Hz), 3.70 (3H, s), 4.43 (1H, m), 5.17 (1H, m),5.3-5.5 (2H, m), 5.63 (1H, ddd, J 10, 5 and 3 Hz), 5.77 (1H, m)

EXAMPLE 5 Compound L

Methyl (1S,2S,4aR,6S,8S,8aS,3'R,5'R)-7'-(1,2,4a,5,6,7,8,8a-octahydro2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]1-naphthalenyl)-3',5'-dihydroxyheptanoate##STR13##

The diol was prepared in the same manner as the diol of Example 2(compound H) but substituting the ketone of Example 4 (compound M) forthe ketone of Example 1.

delta H 0.8-0.9 (6H, m), 1.0-2.0 (24H, m), 2.31 (1H, m), 2.5 (1H, m),2.50 (2H, d, J 6 Hz), 3.33 (1H, br s), 3.73 (3H, s), 3.76 (1H, br s),3.8 (1H, m), 4.25 (1H, m), 5.20 (1H, m), 5.38 (1H, d J 9 Hz), 5.4 (1H,m), 5.65 (1H, m), 5.76 (1H, dd, J 12 and 4 Hz)

EXAMPLE 6 Compound K

(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl}tetrahydro-4'-hydroxy-2H-pyran-2'-one##STR14##

The lactone was prepared in the same manner as the lactone of Example 3(compound G) but substituting the diol of Example 5 (compound L) for thediol of Example 2.

delta H 0.8 (6H, m), 1.18 (6H, s), 1.2-1.45 (6H, m), 1.5-1.8 (9H, m),1.85-2.2 (3H, m), 2.31 (1H, m), 2.50 (2H, m), 2.62 (1H, ddd, J 17, 4 and1 Hz), 2.74 (1H, dd, J 7 and 5 Hz), 4.36 (1H, m), 4.60 (1H, m), 5.18(1H, m), 5.3-5.45 (2H, m), 5.55-4.85 (2H, m)

delta C 9.2, 14.8, 17.8, 23.1, 24.6, 29.6, 31.2, 31.5, 32.9, 35.2, 36.0,37.3, 38.5, 41.8, 42.8, 62.6, 69.4, 76.1, 122.8, 130.8, 132.4, 136.0,170.4, 179.5

EXAMPLE 7 Compound N

Sodium (1S,2S,4aR,6S,8S,8aS,3'R,5'R)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1enyl]-1-naphthalenyl)-3',5'-dihydroxyheptanoate##STR15##

The lactone of Example 6 (compound K) (3.7 mg, 7.6 micromole) wasdissolved in 0.068M sodium hydroxide solution in 2:1 methanol:water (125microL, 8.5 micromole) and left at room temperature for 18 hours.Evaporation of the solvent left the salt as a gum.

EXAMPLE 8 Compound A

(1S,2S,4aR,6S,8S,8aS,4'R,6'R,2"S)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)oxy]-6-[(Z)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one##STR16##

Step 1

(1S,2S,4aR,6S,8S,8aS)-Ethyl8-(tert-Butyldimethylsilyloxy)-6-formyl-2-methyl-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylate(XX)

A solution of dimethylsulphoxide (DMSO) (0.82 ml, 11.6 mmol) indichloromethane (4 ml) was slowly added to a stirred solution of oxalylchloride (0.47 ml, 5.4 mmol) in dichloromethane (5 ml) at -60° C. After5 minutes stirring a solution of (1S,2S,4aR,6S,8S,8a) Ethyl8-(tert-butyldimethylsilyloxy)-6-hydroxymethyl-2-methyl-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylate(general formula XIX) (0.93 g, 2.4 mmol) in dichloromethane (5 ml) wasadded, and the mixture was stirred a further 30 min. Triethylamine (3.7ml, 26.5 mmol) was added, the reaction was allowed to warm to roomtemperature and stirring was then continued for 30 minutes. The mixturewas diluted with dichloromethane (25 ml) and washed with aqueous 0.2Mhydrochloric acid (20 ml) and saturated aqueous sodium bicarbonate (20ml). The organic solution was dried (MgSO₄) and evaporated in vacuo,leaving a pale yellow oil (1.00 g). This was purified by chromatography(silica; hexane: ether 1:1) to yield the title compound (0.72 g, 77%) asa clear oil.

delta H (C₆ D₆) 0.05 (3H,s) and 0.07 (3H,s) (SiMe₂), 1.00 (13H, m 2-Me,t-Bu, 4_(ax) -H), 1.07 (3H, t, J 7 Hz, CH₂ Me), 1.52 (1H, ddd, J 14, 7,and 2 Hz, 7_(ax) -H), 1.63 (1H, td, J 12 and 1Hz, 8a-H), 1.80(1H, tt, J7 and 2 Hz, 6-H), 2.05 (1H, ddt, J 14, 3, and 2Hz, 7_(eq) -H), 2.40 (1H,ddt, J 13, 3, and 2 Hz, 5_(eq) -H), 2.64 (2H, m, 2-H, 4a-H), 2.92 (1H,dd, J 12 and 6 Hz, 1-H), 4.05 (2H, m, CH₂ O), 4.58(1H, m, 8-H), 5.49(2H, m, CH═CH), 9.61 (1H, d, J 1 Hz, CHO)

Step 2

(1S,2S,4aR,6S,8S,8aS)-Ethyl8-(tert-Butyldimethylsilyloxy)-2-methyl-1,2,4a,5,6,7,8,8a-octahydro-6-((Z)prop-1-enyl)naphalene-1-carboxylate(XXI)

A suspension of ethyltriphenylphosphonium bromide (5.00 g, 13.5 mmol) inTHF (17 ml) was stirred at 0° C. under argon while sodiumbis(trimethylsilyl)amide in THF (1.0 M; 13.0 ml, 13.0 mmol) was added.The resulting solution was stirred for 15 min and then cooled to -78° C.A solution of the aldehyde from the previous step (0.83 g, 2.2 mmol) inTHF (8 ml) was added dropwise and stirring continued cold for 1 hour,and then at room temperature for 17 hours. The mixture was diluted witheither (100 ml) and washed with aqueous ammonium chloride (40 ml) andbrine (40 ml), then the organic layer was dried (MgSO₄) and evaporatedin vacuo, leaving a semi-solid (5.3 g). This was purified bychromatography (hexane:ethyl acetate, 50:1) to afford the title compoundas a pale yellow oil (0.84 g, 99%).

delta H (CDCl₃) -0.09 (3H, s) and 0.00 (3H, s) (SiMe₂), 0.86 (d, J 7 Hz,2-Me) and 0.87 (s,t-Bu) (total 12H), 1.26 (3H, t, J 7 Hz, MeCH₂), 1.36(1H, td, J 13 and 5 Hz, 4_(ax) -H), 1.51 (1H, td, J 12 and 2 Hz, 8a-H),1.58 (dd, J 7 and 1.8 Hz, MeCH═CH) and 1.60 (m, 5_(eq) -H)(total 4H),1.70 (1H, ddd, J 14, 5, and 3 Hz, 7_(eq) -H), 1.78 (1H, m, 7_(ax) -H),2.57 (2H, m, 4-H, 2-H), 2.80 (dd, J 12 and 6 Hz, 1-H) and 2.88 (m,6-H)(total 2H), 4.10 (2H, m, CH₂ O), 4.36 (1H, m, 8-H), 5.28 (1H, dqd, J11, 7 and 1.1 Hz, MeCH═CH), 5.37 (1H, br, d, J 10 Hz, 4-H), 5.56 (1H,ddd, J 10,5 and 3 Hz, 3-H), 5.99 (1H, m, MeCH═CH)

Step 3

(1S,2S,4aR,6S,8S,8aS)-1-(tert-Butyldimethylsilyloxy)-8-hydroxymethyl-7-methyl-1,2,3,4,4a,7,8,8a-octahydro-3-((Z)-prop-1-enyl)naphthalene(XV)

The ester from the previous step (0.19 g, 0.48 mmol) was stirred in THF(20 ml) under argon and lithium triethylborohydride in THF (1.0M; 1.0ml, 1.0 mmol) was added. The mixture was warmed to 80° C. and wasstirred at this temperature for 6 hours, fresh portions of lithiumtriethylborohydride (1.0 ml) being added hourly. The temperature waslowered to 0° C. and water (1 ml) was cautiously added, followed byaqueous 3M sodium hydroxide (2 ml) and 30% aqueous hydrogen peroxide (2ml). The resulting gel was stirred at room temperature for 2h and thenpoured onto brine (15 ml) and extracted with ether (2×20 ml). Thecombined ethereal solutions were dried (MgSO₄) and evaporated in vacuo.The residue was purified by chromatography (hexane:ethyl acetate, 25:1)to afford the title compound as a colourless oil (0.12 g, 71%).

delta H 0.07 (3H, s) and 0.08 (3H,s) (SiMe2), 0.91 (9H, s, t-Bu), 0.96(3H, d, J 7 Hz, 7-Me), 1.00 (1H, s, removed by D₂ O, OH), 1.13 (1H, td,J 11 and 2 Hz, 8a-H), 1.32 (1H, td, J 13 and 5 Hz, 4_(ax) -H), 1.58 (dd,J 7 and 1.9 Hz, MeCH═CH) and 1.6 (m, 2_(eq) -H, 4_(eq) -H)(total of 5H),1.79 (1H, ddd, J 14,5 and 1.9 Hz, 2_(ax) -H), 2.02 (1H, tt, J 11 and 5Hz, 8-H), 2.54 (2H, m, 4a-H, 7-H), 2.83 (1H, m, 3-H), 3.49 (1H, td, J 11and 6 Hz, CHH'OH), 3.90 (1H, m, CHH'OH), 4.01 (1H, m, 1-H), 5.30 (1H,dqd, J 10,7, and 1 Hz, MeCH═CH), 5.36 (1H, br d,J 10 Hz, 5-H), 5.64 (1H,ddd, J 10,5, and 1.6 Hz, 6-H), 5.99 (1H, m, MeCH═CCH)

Step 4

(1S,3S,4aR,6S,8S,8aS)-1-Hydroxy-8-hydroxymethyl-7-methyl-1,2,3,4,4a,7,8,8a-octahydro-3-((Z)-prop-1-enyl)naphthalene(VII)

The alcohol from the previous step (0.54 g, 1.54 mmol) was stirred atroom temperature under argon in 19:1 acetonitrile: aqueous hydrofluoricacid (40%) (15 ml) for 15 hours. Ether (150 ml) was added followed bysaturated aqueous sodium bicarbonate solution (50 ml). The etherealsolution was dried (MgSO₄) and the solvent removed to give the titlecompound as an off-white solid (0.35 g, 97%). A small sample wasrecrystallized (dichloromethane/hexane) for analysis.

m.p., 131°-133° C.

nu_(max) (CH₂ Cl₂), 3620,3495 cm⁻¹

delta H 0.82 (3H, d, J 7 Hz, 7-Me), 1.30 (1H, td, J 11 and 2 Hz, 8a-H),1.33 (1H, td, J 13 and 5 Hz, 4_(ax) -H), 1.6(m, 4_(eq) -H) and 1.63 (dd,J 7 and 1.8 Hz, MeCCH═CH (total of 4H), 1.80 (1H, ddd, J 14,6, and 3 Hz,4_(eq) -H), 1.95 (1H, m, 2_(ax) -H), 2.03 (1H, m, 8-H), 2.40 (1H, m,7-H), 2.41 (1H, br s, removed by D₂ O, OH), 2.53 (1H, m, 4a-H), 2.76(1H, br s, removed by D₂ O, OH'), 2.88 (1H, m, 3-H), 3.65 (1H, dd, J 10and 1.4 Hz, CHH'OH), 3.76 (1H, t, J 10 Hz, CHH'OH), 4.24 (1H, m, 1-H),5.37 (1H, br d, J 10 Hz, 5-H), 5.43 (1H, dqd, J 11,7, and 1.4 Hz,MeCH'CH), 5.56 (1H, ddd, J 10,5, and 2.6, 6-H), 6.00 (1H, m, MeCH═CH)

Found: C, 75.93; H, 10.06 Calculated for C₁₅ H₂₄ O₂ : C, 76.22; H, 10.24

Step 5

(1S,3S,4aR,7S,8S,8aS,2'S)-8-Formyl-7-methyl-1,2,3,4,4a,7,8,8a-octahydro-3-((Z)-prop-1-enyl)-1-naphthalenyl 2'-methylbutyrate(XII)

The title compound was obtained from the diol of step 4 in a similarmanner to that in which the diol of Example 1, step 3 was transformedinto the aldehyde (Example 1, steps 4 and 5), that is by protection ofthe primary alcohol, acylation of the secondary alcohol, deprotection ofthe alcohol, and oxidation.

delta H 0.88(3H, t, J 7 Hz, MeCH₂), 0.97 (3H, d, J 7 Hz, 7-Me), 1.13(3H, d, J 7 Hz, MeCHCO), 1.35-2.05 (7H,m), 1.59 (3H, dd, J 7 and 1.5 Hz,MeCH═CH), 2.30 (1H, sextet, J 7 Hz, MeCHCO₂), 2.52 (1H, br t, J 12 Hz,4a-H), 2.70 (2H, m, 7-H,8-H), 2.91 (1H, m, 3-H), 5.36 (2H, m, 1-H,MeCH═CH), 5.42 (1H, br d, J 10 Hz, 5-H), 5.62 (1H, m, 6-H), 5.79 (1H, brt, J 10 Hz, MeCCH═CH), 9.74 (1H, d, J 2 Hz, CHO)

Step 6

(1R,2S,4aR,6S,8S,8aS,3'R,2"S)-Methyl3-tert-Butyldimethylsilyloxy-7'-(8-tert-butyldimethylsilyloxy-2-methyl-8-(2"-methylbutyryloxy)-1,2,4a,5,6,7,8,8a-octahydro-6-((Z)-prop-1-enyl)-1-naphthalenyl)-5'-oxohept-6'-enoate(XIV)

The aldehyde from the previous step (91 mg, 0.29 mmol), theketo-phosphonate (general formula XIII) (160 mg, 0.42 mmol) and lithiumchloride (18 mg, 0.42 mmol) were stirred at room temperature under argonin acetonitrile (0.22 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.055ml, 0.37 mmol) was added. The mixture was stirred at room temperaturefor 80 hours and then diluted with ethyl acetate (25 ml) and washed withaqueous 0.5M phosphoric acid (10 ml) and brine (10 ml). The combinedaqueous layers were extracted with ethyl acetate (25 ml) and thecombined organic layers were dried (MgSO₄) and evaporated in vacuo. Theresidue (245 mg) was purified by chromatography (hexane:ethyl acetate,19:1-9:1), affording the title compound as a colourless oil (32 mg,20%).

delta H 0.02 (3H,s) and 0.06 (3H,s) (SiMe2), 0.83 (9H, s, t-Bu), 0.85(3H, t, J 7 Hz, MeCH₂), 0.95 (3H, d, J 7 Hz, 2-Me), 1.11 (3H, d, J 7 Hz,MeCHCO), 1.3-2.1 (7H,m), 1.55 (3H, dd, J 7 and 1.5 Hz, MeCH═CH), 2.26(sextet, J 7 Hz, CHCO₂) and 2.31 (m,1-H)(total of 2 H), 2.4-2.7 (4H, m,4a-H,2-H, and 2'H), 2.75 (2H, m, 4'H, 2.89 (1H, br, 6-H), 3.63 (3H, s,MeO₂ C), 4,58 (1H, m, 3'-H), 4.88 (1H, m, 8-H), 5.30 (1H, dq, J 11 and 7Hz, MeCH═CH), 5.42 (1H, br d, J 10 Hz, 4-H), 5.61 (1H, ddd, J 10,5, and3 Hz, 3-H), 5.74 (1H, m, MeCH═CH), 5.98 (1H, d, J 16 Hz, 6'H), .678 (1H,dd, J 16 and 10 Hz, 7'-H)

The lactone of Example 8 (compound A) (4.7 mg, 11 micromole) wasdissolved in 0.067M sodium hydroxide in 2:1 methanol:water (180 microL,12 micromole) and left at room temperature for 14 hours. Diethyl ether(1 mL) and water (1mL) were added and separated, the aqueous layerwashed with a more diethyl ether (1 mL), then evaporated. The residuewas taken up in acetone (2 mL), filtered and evaporated to afford thetitle salt as a glass.

EXAMPLE 10 Compound C

(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(Z)-prop-1-enyl]-1naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one##STR17##

The lactone was prepared in a similar manner to the lactone of Example 8(compound A) but substituting 2,2-dimethylbutyryl chloride for2-methylbutyric anhyride in step 5.

Step 7

(1S,2S,4aR,6S,8S,8aS,4'R,6'R,2"S)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)oxy]-6-[(Z)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one(I)

The title compound was obtained from the enone of step 6 in a mannersimilar to that in which the pyranone of Example 3 (compound G) wasobtained from the enone of Example 1, step 6.

delta H 0.86 (3H, d, J 7 Hz, 2-Me) and 0.88 (3H, t, J 7 Hz, MeCH2), 1.11(3H, d, J 7 Hz, MeCHCO), 1.2-2.4 (17H,m), 1.57 (3H, dd, J 7 and 1.7 Hz,MeCH═CH), 2.51 (1H, br t, 11 Hz, 4a-H), 2.60 (1H, dd, J 18 and 4 Hz,3'-H), 2.74 (1H dd, J 18 and 5 Hz, 3'-H'), 2.87 (1H, m, 6-H), 4,38 (1H,m, 4'-H), 4.60 (1H, m, 6'-H), 5.20 (1H, m, 8-H), 5.33 (1H, m, MeCH═CH),5.38 (1H, br d, 4-H), 5.63 (1H, m, 3 -H), 5.78 (1H, m, MeCH═CH)

EXAMPLE 9 Compound B

Sodium (1S,2S,4aR,6S,8S,8aS,3'R,5'R,2"S)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8[(2"-methyl-1"-oxobutyl)oxy]-6-[(Z)-prop-1-enyl]-1-naphthalenyl)-3',5'-dihydroxyheptanoate##STR18##

delta H 0.82 (3H, t, J 7 Hz), 0.86 (3H, d, J 7 Hz), 1.14 (6H, s),1.15-1.45 (6H, m), 1.5-2.1 (12H, m), 2.30 (1H, m), 2.50 (1H, br t, 12Hz), 2.60 (1H, ddd, J 18, 4 and 1Hz), 2.73 (1H, dd, J 18 and 5 Hz), 2.87(1H, m), 4.37 (1H, m),4.60 (1H, m), 5.19 (1H, m), 5.2 -5.5 (2, m), 5.65(1H, m), 5.79 (1H, m)

EXAMPLE 11 Compound D

(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-4'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-but-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one##STR19##

The lactone was prepared in a similar manner to the lactone of Example 6(compound K) but substituting propyl phenylsulphone in place of ethylphenylsulphone in the first step.

delta H 5.75 (1H, dd, J 15 and 8 Hz), 5.66 (1H, m), 5.40 (1H, d, J 8Hz), 5.38 (1H, m), 5.21 (1H, br d, J 2 Hz), 4.60 (1H, br m), 4.37 (1H,quintet, J 3 Hz), 2.74 (1H, dd, J 18 and 5 Hz), 2.61 (1H, ddd, J 18, 4and 1 Hz), 2.49 (1H, m), 2.31 (1H, m), 2.03-1.57 (12H, m), 1.54-1.15(12H, m), 0.98-0.80 (9H, m)

delta C 177.4, 170.1, 133.9, 132.4, 130.8, 130.4, 76.1, 69.4, 62.6,42.9, 41.8, 38.5, 37.5, 37.3, 36.0, 35.3, 32.9, 31.4, 31.2, 29.6, 25.7,24.6, 23.1, 14.8, 14.3, 14.0

EXAMPLE 12 Compound E

(1S,2S,4aR,6S,8S,8aS,4'R,6'R,2"S)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8[(2"-methyl-1"-oxobutyl)oxy]-6-[(E)-hex-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one##STR20##

The lactone was prepared in a similar manner to the lactone of Example 6(compound K) but substituting n-pentyl phenylsulphone in place of ethylphenylsulphone in the first step, and (S)-2-methylbutyryl anhydride inplace of the acid chloride in step 5.

delta H 5.7 (1H, dd, J 14 and 7 Hz), 5.65 (1H, m), 5.4 -53. (2H, m), 5.2(1H, br d, J 2 Hz), 4.6 (1H, m), 4.35 (1H, quintet, J 3 Hz), 2.8-2.6(2H, ddd, J 14, 6 and 4 Hz), 2.6-2.2 (5H, m), 2.0-1.2 (17H, m), 1.1 (4H,m+d, J 7 Hz), 0.9-0.8 (9H, m)

delta C 176.3, 170.5, 134.5, 132.5, 130.8, 128.8, 76.2, 69.4, 62.4,41.6, 38.5, 37.5, 37.3, 35.9, 35.3, 32.8, 32.3, 31.7, 31.5, 31.2, 29.6,26.6, 23.0, 22.2, 16.2, 14.8, 13.9, 11.6

nu_(max) (neat) 2920, 1720, 1700 cm⁻¹

EXAMPLE 13 Compound F

(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)ocy]-6-[(E)-hex-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one##STR21##

The lactone was prepared in a similar manner to the lactone of Example 6(compound K) but substituting pentyl phenylsulphone in place of ethylphenylsulphone in the first step.

delta H 5.76 (1H, dd, J 15 and 8 Hz), 5.66 (1H, ddd, J 10, 5 and 3 Hz),5.42-4.30 (2H, m), 5.21 (1H, m), 4.61 (1H, m), 4.38 (1H, m), 2.78 (1H,dd, J 17 and 5 Hz), 2.62 (1H, dd, J 17 and 4 Hz), 2.52-1.22 (23H, m),1.16 (3H, s), 1.15 (3H, s), 0.98-0.80 (9H, m)

delta C 177.4, 170.0, 134.7, 132.4, 130.8, 128.9, 76.1, 69.4, 62.6,42.9, 41.8, 41.7, 38.5, 37.6, 37.3, 36.0, 35.3, 32.9, 32.3, 31.8, 31.5,31.2, 29.6, 26.6, 24.9, 23.1, 14.8, 13.9, 9.2, 9.2

EXAMPLE 14 Compound P

(1S,2S,4aR,6S,8S,8aS,4'R,6'R,2"S)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8[(2"-methyl-1"-oxobutyl)oxy]-6-[3-henyl-(E)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one##STR22##

The lactone was prepared in a similar manner to the lactone of Example 6(compound K) but substituting 2-phenylethyl phenylsulphone in place ofethyl phenylsulphone in the first step, and (S)-2-methylbutyrylanhydride in place of the acid chloride in step 5.

delta H 7.31-7.14 (5H, m), 5.88 (1H, dd, J 15 and 8 Hz, 5.68 (1H, m),5.56 (1H, dr, J 15 and 7 Hz), 5.41 (1H, m), 5.25 (1H, s), 4.38 (1H, m),3.32 (2H, br d, J 7 Hz), 2.75 (1H, dd, J 17 and 5 Hz), 2.67-1.16 (21H,m), 1.12 (3H, d, J 7 Hz), 0.92-0.85 (6H, m)

delta C 176.2, 170.1, 140.7, 136.3, 134.6, 132.5, 130.7, 128.3, 128.2,127.2, 125.6, 76.0, 69.3, 62.6, 41.7, 41.5, 38.9, 38.5, 37.5, 37.3,36.0, 35.8, 35.3, 32.6, 31.5, 31.2, 26.6, 23.0, 16.2, 14.8, 11.6

EXAMPLE 15 Compound O

(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8[(2"-dimethyl-1"-oxobutyl)oxy]-6-[3-phenyl-(E)-prop-1-enyl]-1naphthalenyl)ethyl}tetrahydro-4'-hydroxy-2H-pyran-2'-one##STR23##

The lactone was prepared in a similar manner to the lactone of Example 6(compound K) but substituting 2-phenylethyl phenylsulphone in place ofethyl phenylsulphone in the first step.

delta H 7.32-7.15 (5H, m), 5.94 (1H, dd, J 15 and 8 Hz), 5.66 (1H, ddd,J 10, 5 and 3 Hz), 6.63 (1H, dt, J 15 and 7 Hz), 5.40 (1H, br d, J 10Hz), 5.23 (1H, m), 4.61 (1H, m), 4.38 (1H, m), 3.32 (2H, br d, J 7 Hz),2.75 (1H, dd, J 18 and 5 Hz), 2.62 (1H, ddd, J 18, 4 and 1 Hz), 2.64-1.2(18H, m), 1.16 (6H,s), 0.88-0.82 (6H, m)

delta C 177.4, 170.0, 140.8, 136.5, 135.0, 132.5, 130.7, 128.3, 128.2,127.1, 125.7, 76.1, 69.4, 62.7, 42.9, 41.8, 38.9, 38.5, 37.5, 37.3,36.0, 35.9, 35.4, 33.2, 32.9, 31.5, 31.2, 29.7, 23.1, 14.8, 9.2

EXAMPLE 16 Compound R

(1S,4aR,6S,8S,8aS,4'R,6'R,2"S)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-8-[(2"-methyl-1"-oxobutyl)oxy]-6-methyl-1naphthalenyl)ethyl}tetrahydro-4'-hydroxy-2H-pyran-2'-one##STR24##

The intermediate alcohol (1S,4aR,6S,8S,8aS)-1,2,4a,5,6,7,8,8a-octahydro-8-hydroxy-1-hydroxymethyl-2-methylnaphthalene(general formula XXIII, R⁵ =hydrogen, R¹⁰ =ethyl) was prepared accordingto the literature method (A. H. Davidson, C. D. Floyd, A. J. Jones, C.N. Lewis, and P. L. Myers, J. Chem. Soc., Chem. Commun., 1987, 1786) butsubstituting penta-2,4-dienyl bromide for hexa-2,4-dienyl bromide. Thiswas then transformed into the lactone in a manner similar to that usedfor the synthesis of the lactone of Example 6 (compound K) butsubstituting (S)-methyl butyric anhydride for dimethylbutyryl chloride.

delta H 5.65 (1H, m), 5.44 (1H, br d, J 10 Hz), 5.30 (1H, m), 4.62 (1H,m), 4.37 (1H, m), 2.75 (1H, dd, J 17 and 5 Hz), 2.62 (1H, ddd, J 17, 4and 1 Hz), 2.75 -1.2 (20H, m), 1.16-1.10 (6H, m), 0.94-0.88 (3H, t, J 7Hz)

delta C 176.2, 170.1, 132.4, 125.5, 76.0, 69.0, 65.8, 62.8, 47.2, 38.6,38.5, 35.9, 35.6, 33.7, 32.4, 31.8, 29.7, 27.0, 26.6, 20.9, 16.4, 15.2,11.7

EXAMPLE 17 Compound S

(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-(acetoxy)-6-[(Z)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one##STR25##

The lactone was prepared in a similar manner to the lactone of Example 8(compound A) but substituting acetic anhydride in place of2-methylbutyric anhydride in step 5.

delta H 0.85 (1H, d, J 7 Hz), 1.2-2.2 (16H, m), 2.03 (3H, s), 2.30 (1H,m), 2.52 (1H, br, t, J 12 Hz), 2.62 (1H, ddd, J 18, 4 and 1 Hz), 2.75(1H, dd, J 18 and 5 Hz), 2.88 (1H, m), 4.38 (1H), m), 4.66 (1H, m), 5.17(1H, m), 5.35 (1H, m), 5.38 (1H, br d, J 10 Hz), 5.67 (1H, dd, J 10, 5and 2 Hz), 5.76 (1H, br t, J 10 Hz)

EXAMPLE 18 Compound T

(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8[(2"-dimethyl-1"-oxobutyl)oxy]-6-[3-methyl-(E)-but-1-enyl]-1-naphthalenyl)ethyl)tetrahydro-4'-hydroxy-2H-pyran-2'-one##STR26##

The lactone was prepared in a similar manner to the lactone of Example 6(compound K) but substituting (2-methylpropyl) phenylsulphone in placeof ethyl phenylsulphone in the first step.

delta H 5.72 (1H, dd, J 15 and 9 Hz), 5.65 (1H, m), 5.40 (1H, br d, J 10Hz), 5.30 (1H, dd, J 15 and 7 Hz), 5.24 (1H, m), 4.62 (1H, m), 4.39 (1H,quintet, J 3 Hz), 2.75 (1H, dd, J 17 and 5 Hz), 2.61 (1H, ddd, J 17, 3and 1 Hz), 2.48-1.16 (25H, m), 0.98-0.82 (12H, m)

delta C 174.0, 170.1, 136.4, 132.6, 131.9, 131.0, 76.1, 69.6, 62.8,43.0, 42.1, 38.6, 38.1, 37.3, 35.7, 35.4, 35.3, 33.0, 31.4, 29.7, 24.8,23.5, 23.0, 15.1, 9.6

EXAMPLE 19 Compound U

(1R,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-(E)-ethenyl}-tetrahydro-4'-hydroxy2H-pyran-2'-one##STR27##

The lactone was prepared in a similar manner to the lactone of Example 6(compound K) but but omitting the reduction with sodium hydrogentelluride, in step 7.

delta H 5.8-5.6 (3H, m), 5.5-5.3 (3H, m), 5.15 (1H, ddd, J 12, 7 and 3Hz), 5.0 (1H, d, J 2 Hz), 4.37 (1H, m), 2.74 (1H, dd, J 17 and 5 Hz),2.62 (1H, ddd, J 17, 4 and 1 Hz), 2.6-2.1 (4H, m), 2.0-1.5 (9H, m),1.4-1.2 (3H, m), 1.17 (3H, s), 1.13 (3H, s), 0.92 (3H, d, J 7 Hz), 0.85(3H, t, J 7 Hz)

delta C 177.2, 170.1, 136.3, 135.9, 132.6, 130.6, 129.6, 132.1, 76.9,70.3, 62.8, 42.0, 41.6, 38.5, 37.4, 36.8, 36.3, 35.7, 35.6, 32.9, 30.7.24.8, 24.7, 18.0, 16.5, 9.2

EXAMPLE 20 Compound W

(1S,2S,4aR,6S,8S,8aS,4'R,6'R,2"S)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)oxy]-6-propyl-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one##STR28##

The lactone was isolated as a side product in the synthesis of compoundG (Example 3) and was purified by chromatography on C-18 reverse phasesilica, eluting with methanol:water (7:3).

delta H 0.85 (3H, d, J 7 Hz), 0.87 (3H, t, J 7 Hz), 0.91 (3H, t, J 7Hz), 1.13 (3H, d, J 7 Hz), 1.2-2.6 (23H, m), 2.58 (1H, ddd, J 18, 4, and2 Hz), 2.74 (1H, dd, J 18 and 5 Hz), 4.38 (1H, m), 4.60 (1H, m), 5.18(1H, m), 5.38 (1H, br d, J 10 Hz), 5.64 (1H, ddd, J 10, 5 and 2 Hz)

EXAMPLE 21 Pharmacology

IN VITRO DETERMINATION OF INHIBITORY POTENTIAL OF HMG-CoA REDUCTASEINHIBITORS

HMG-CoA reductase was induced in rats by feeding a normal dietsupplemented with 3% cholestyramine resin for one week prior tosacrifice. The livers were excised from the sacrificed rats andmicrosomal pellets prepared by the method of Kleinsek et al, Proc. Natl.Acad. Sci. USA, 74 (4), pp 1431-1435, 1977. Briefly, the livers wereimmediately placed in ice-cold buffer I (see below) and homogenised in aPotter-Elvehjem type glass/TEFLON homogeniser (10 passes at 1000 rpm).(The word TEFLON is a trade mark for p.t.f.e.) The homogenate wascentrifuged twice at 20,000×g to remove debris. The supernatant wascentrifuged at 100,000×g for 75 minutes, the microsomal pelletresuspended in buffer II (see below) and centrifuged at 100,000×g for 75minutes. The resultant pellet was stored at -70° C. until required forassay purposes.

    ______________________________________                                        Buffer I           Buffer II                                                  ______________________________________                                        50 mM KPO.sub.4 pH 7.0                                                                           50 mM KPO.sub.4 pH 7.0                                     0.2 M sucrose      0.2 M sucrose                                              2 mM DTT           2 mM DTT                                                                      50 mM EDTA                                                 ______________________________________                                    

Assay of HMG-CoA Reductase Activity and Determination of Activity ofInhibitors

Membrane bound enzyme isolated as above is used for determining theactivity of inhibitors. The assay is performed in a total volume of 300μl in 100 mM KPO₄ pH 7.2 buffer, containing 3 mM MgCl₂, 5 mMglucose-6-phosphate, 10 mM reduced glutathione, 1mM NADP, 1 unitglucose-6-phosphate dehydrogenase, and 1 mg/ml BSA, with resuspendedenzyme. Putative inhibitors are converted to sodium salts, thendissolved in dimethylsulphoxide and 10 μl aliquots added to theincubation.

The assay is pre-incubated at 37° C. for 10 minutes and initiated by theaddition of 0.1 μCi 3-hydroxy-3-methyl-[3-¹⁴ C]glutaryl coenzyme A (52Ci/Mole) followed by incubating the complete reaction at 37° C. for 10minutes. At the end of this period the reaction is stopped by adding 300μl of a 10 mM mevalonolactone solution in 0.1 M hydrochloric acid andthe mevalonic acid product allowed to lactonise for a further period of30 minutes. The product is then isolated by chromatography using Bio-Rex5 resin and the enzyme activity quantified by liquid scintillationspectrophotometry.

Appropriate controls are included in the assay and IC₅₀ values obtainedby graphical means. The results are shown in Table I below.

EXAMPLE 22 Pharmacology

ASSAY FOR THE INHIBITION OF CHOLESTEROL BIOSYNTHESIS IN CULTURED CELLS

Human hepatoma (HEP G₂) or fibroblastic (HES-9) cells were grown inDulbecco's modified Eagle's medium (DMEM) with 10% foetal calf serum, in6 cm tissue culture dishes until approaching confluence (approximately 4days). The medium was changed to DMEM with 1% foetal calf serum 24 hoursprior to experimentation.

Test compounds that are salts were dissolved in aqueous, physiologicalbuffer. Lactones and esters were dissolved in dimethylsulphoxide.

Test compound were added to the cell monolayers concurrently with 2-¹⁴C-acetate (5 μCi/ml of incubation volume); control samples receivingvehicle together with radioisotope. The incubation was continued for 3hours at 37° C.

Incorporation of ¹⁴ C-acetate into non-saponifiable,digitonin-precipitable sterols in control samples continued in a linearmanner beyond 3 hours.

The IC₅₀ for inhibition of sterol synthesis by test compounds wasmeasured from plots of % inhibition (compared to controls) versus logconcentration, using at least 5 concentrations of inhibitor.

This assay, therefore, measures the ability of test substances toinhibit intracellular synthesis of cholesterol.

Representative of the intrinsic HMG-CoA reductase inhibitory activitiesof the claimed compound are the IC₅₀ s, tabulated below for a number ofthe compounds of the invention in both tests, expressed in nonomolarconcentrations.

                  TABLE 1                                                         ______________________________________                                        Example Number  Test A  Test B (HEP G.sub.2)                                  ______________________________________                                        3 (Compound G)   4      25                                                    (after hydrolysis)                                                            7 (Compound N)   3       7                                                    9 (Compound B)  15      60                                                    Dihydromevinolin                                                                              30      40                                                    (prior art)                                                                   ______________________________________                                    

Examples of unit dosage compositions are as follows:

EXAMPLE 23 Capsules

    ______________________________________                                                                          Per 10,000                                  Ingredients       Per Capsule     Capsules                                    ______________________________________                                        1.    Active ingredient                                                                             40.0    mg    400  g                                          (Cpd of Formula I)                                                      2.    Lactose         150.0   mg    1500 g                                    3.    Magnesium stearate                                                                            4.0     mg    40   g                                                          194.0   mg    1940 g                                    ______________________________________                                    

Procedure for capsules

Step 1. Blend ingredients No. 1 and No. 2in a suitable blender.

Step 2. Pass blend from Step 1 through a No. 30 mesh (0.59 mm) screen.

Step 3. Place screened blend from Step 2 in a suitable blender withingredient No. 3 and blend until the mixture is lubricated.

Step 4. Fill into No. 1 hard gelatin capsule shells on a capsulemachine.

EXAMPLE 24 Tablets

    ______________________________________                                                                          Per 10,000                                  Ingredients       Per Tablet      Tablets                                     ______________________________________                                        1.      Active ingredient                                                                           40.0    mg    400  g                                            (Cpd of Form. I)                                                      2.      Corn Starch   20.0    mg    200  g                                    3.      Alginic acid  20.0    mg    200  g                                    4.      Sodium alginate                                                                             20.0    mg    200  g                                    5.      Magnesium stearate                                                                          1.3     mg    13   g                                                          101.3   mg    1013 g                                    ______________________________________                                    

Procedure for tablets

Step 1. Blend ingredients No. 1, No. 2, No. 3and No. 4 in a suitablemixer/blender.

Step 2. Add sufficient water portionwise to the blend from Step 1 withcareful mixing after each addition. Such additions of water and mixinguntil the mass is of a consistency to permit its conversion to wetgranules.

Step 3. The wet wall is converted to granules by passing it through anoscillating granulator using a No. 8 mesh (2.38 mm) screen.

Step 4. The wet granules are then dried in an oven at 140° F. (60° C.)until dry.

Step 5. The dry granules are lubricated with ingredients No. 5.

Step 6. The lubricated granules are compressed on a suitable tabletpress.

EXAMPLE 25 Intramuscular Injection

    ______________________________________                                        Ingredient          Per ml. Per liter                                         ______________________________________                                        1.    Formula I compound                                                                              10.0 mg 10 g                                                Active ingredient                                                       2.    Istonic buffer    q.s.    q.s.                                                solution pH 4.0.                                                        ______________________________________                                    

Procedure

Step 1. Dissolve the active ingredient in the buffer solution.

Step 2. Aseptically filter the solution from Step 1.

Step 3. The sterile solution is now aseptically filled into sterileampoules.

Step 4. The ampoules are sealed under aspetic conditions.

EXAMPLE 26 Suppositories

    ______________________________________                                                                          Per                                         Ingredients        Per Supp.      1,000 Supp                                  ______________________________________                                        1.    Formula I compound                                                                             40.0    mg   40    g                                         Active ingredient                                                       2.    Polyethylene Glycol                                                                            1350.0  mg   1,350 g                                         1000                                                                    3.    Polyethylene Glycol                                                                            450.0   mg   450   g                                         4000                                                                                           1840.0  mg   1,840 g                                   ______________________________________                                    

Procedure

Step 1. Melt ingredient No. 2 and No. 3 together and stir until uniform.

Step 2. Dissolve ingredient No. 1 in the molten mass from Step 1and stiruntil uniform.

Step 3. Pour the molten mass from Step 2 into suppository moulds andchill.

Step 4. Remove the suppositories from moulds and wrap.

We claim:
 1. A compound of either of general formulae I and II ##STR29##wherein: R¹ represents a C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl(C₁₋₈) alkyl, C₂₋₈ alkenyl, or C₁₋₆ alkyl substituted phenyl group;R²represents a C₂₋₈ alkenyl, C₂₋₈ alkynyl, group or C₂₋₅ alkenyl, or C₂₋₅alkynyl group substituted with a phenyl or substituted phenyl group; R³represents a hydrogen atom or a substituent R⁴ or M; R⁴ represents aC₁₋₅ alkyl group, or a C₁₋₅ alkyl group substituted with a group chosenfrom substituted phenyl, dimethylamino and acetylamino; whereinsubstituted phenyl is phenyl substituted with C₁₋₆ alkyl, C₁₋₆ alkoxy,hydroxy, thiol amino, halo, trifluoromethyl or nitro; R⁵ represents ahydrogen atom or a methyl or ethyl group; M represents a cation capableof forming a pharmaceutically acceptable salt; Q represents C═O or CHOH;and each of a, b, c, and d is independently a single or double bondexcept that when a and c are double bonds then b is a single bond.
 2. Acompound as claimed in claim 1, which has one or more of the followingsubstituents independently or in any combination:R¹ represents C₄₋₆branched alkyl; R² represents C₂₋₅ alkenyl or C₂₋₅ alkenyl substitutedwith phenyl or substituted phenyl; R³ is R⁴ ; R⁴ represents C₁₋₅ alkyl;Q represents CHOH; and/or b and d are both single bonds, and one or bothof a and c are double bonds.
 3. A compound according to claim 1, whereinR¹ represents a C₄₋₆ branched alkyl group; R² represents a C₂₋₆ alkenylgroup; each of a and c independently represents a single or double bond;and each of b and d represents a single bond.
 4. A compound selectedfrom the group consistingof:(1S,2S,4aR,6S,8S,8aS,4'R,6'R,2"S)-6'-(2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8[(2"-methyl-1"-oxobutyl)oxy]-6-[(Z)-prop-1-enyl]-1-naphthalenyl)-ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one;Sodium(1S,2S,4aR,6S,8S,8aS,3'R,5'r,2"S)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)oxy]-6-[(Z)-prop-1-enyl]-1-naphthalenyl)-3',5'-dihydroxyheptanoate;(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-["2",2"-dimethyl-1"-oxobutyl)-oxy]-6[(Z)-prop-enyl]-1-naphthalenyl)ethyl}-tetra-hydro-4'-hydroxy-2H-pyran-2'-one;(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[("2",2"-dimethyl-1"-oxobutyl)-oxy]-6-[(E)-but-1-enyl]-1-naphthalenyl)ethyl}-tetra-hydro-4'-hydroxy-2H-pyran-2'-one;(1S,2S,4aR,6S,8S,8aS,4'R,6'R,2"S)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)-oxy]-6-[(E)-hex-1-enyl]-1-naphthalenyl)ethyl}-tetra-hydro-4'-hydroxy-2H-pyran-2'-one;or(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8a-octahydro-2-methyl-8-["2",2"-dimethyl-1"oxobutyl)-oxy]-6-[(E)]hex-1-naphthalenyl)ethyl)-tetra-hydro-4'-hydroxy-2H-pyran-2'-one.5. A compound according to claim 3, wherein R¹ represents a C₄₋₅branched alkyl group; R² represents (E)-prop-1-enyl; and R⁵ representsmethyl.
 6. A compound selected from the group consistingof:(1S,2S,4aR,6S,8S,8aS,4'R,6'R,2"s)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)-oxy]-6[(E)-prop-1-enyl]-1-napthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one;Methyl(1S,2S,4aR,6S,8S,8aS,3'R,2"S)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[2"-methyl-1"-oxo-butyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3',5'-dihydroxyheptanoate;Methyl(1S,2S,4aR,6S,8S,8aS,3'R,2"S)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[(2"-methyl-1"-oxobutyl)-oxy]-3[(E)-prop-1-enyl]-1-naphthalenyl)-3'-hydroxy-5'-oxoheptanoate;(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-{2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[("2",2"-dimethyl-1"-oxobutyl)-oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)ethyl)-tetra-hydro-4'-hydroxy-2H-pyran-2'-one;Methyl(1S,2S,4aR,6S,8S,8aS,3'R,5'R)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-["2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3',5'-dihydroxyheptanoate;Methyl(1S,2S,4aR,6S,8S,8aS,3'R)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-["2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3'-hydroxy-5'-oxoheptanoate;or Sodium(1S,2S,4aR,6S,8S,8aS,3'R,5'R)-7'-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[("2",2"-dimethyl-1"-oxobutyl)oxy]-6-[(E)-prop-1-enyl]-1-naphthalenyl)-3',5'-dihydroheptanoate.7. A compound according to claim 1, wherein R¹ represents a C₄₋₆branched alkyl group; R² represents a C₂₋₅ alkenyl substituted by aphenyl or substituted phenyl group; each of a and c independentlyrepresents a single or double bond; and each of b and d represents asingle bond.
 8. A compound according to claim 7, wherein R¹ represents abranched C₄ alkyl group; R² represents prop-1-enyl; R³ represents methylor ethyl; R⁵ represents methyl; and Q represents the group CHOH.
 9. Acompound selected form the group consistingof:1S,2S,4aR,6S,8S,8aS,4'R,6'R,2"S)-6'-(2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-[2"-methyl-1"-oxobutyl)oxy]-6-[3-phenyl-(E)-prop-1-enyl]-1-naphthalenyl)ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one;or(1S,2S,4aR,6S,8S,8aS,4'R,6'R)-6'-(2-(1,2,4a,5,6,7,8,8a-octahydro-2-methyl-8-("2",2"-dimethyl-1"-oxobutyl)-oxy]-6-[3-phenyl-(E)-prop-1-enyl]-1-naphthalenyl)-ethyl}-tetrahydro-4'-hydroxy-2H-pyran-2'-one.10. A pharmaceutical composition comprising a compound as defined in anyone of claims 1 to 9, or a mixture of such compounds, and apharmaceutically acceptable carrier therefor.
 11. A composition asclaimed in claim 10 comprising a pharmaceutically acceptable non-toxiccation polymer capable of binding bile acids in a non-reabsorbable formin the gastrointestinal tract.
 12. A compound of the formula ##STR30##wherein R₂ and R₅ and a, b, c and d are as defined in claim
 1. 13. Acompound of the formula: ##STR31## wherein R¹, R², R⁴ and R⁵, and a, band c are as defined in claim 1 and P² is t-butyldimethylsilylprotecting group.
 14. A compound of the formula ##STR32## wherein R¹ andR², a, b and c are as defined in claim 1.